Criteria Specification Registry

Criteria Specification (CSpec) Registry is intended to provide access to the Criteria Specifications used and applied by ClinGen Variant Curation Expert Panels and biocurators in the classification of variants.

For general information about the ClinGen Expert Panels and Variant Curation please visit: Clinical Domain Working Groups. For specific inquiries regarding content correction or adding a new criteria specification refer to the Help page.

Should you encounter any issues regarding the data displayed, lack of functionality or other problems, please let us know by contacting us via email.

Criteria Specification

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1.0

Description : The following criteria are for classic or attenuated familial adenomatous polyposis only and does not apply to Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS, MONDO:0017790). The preferred transcript for coding, intronic and promoter 1A variants is NM_000038.6 (MANE transcript). The NM_001127510.2 transcript differs from NM_000038.6 in the number of "non-coding" exons in the 5' region, which results in different exon numbering (in NM_000038.6 there is only one non-coding exon, in NM_001127510.2 there is one additional non-coding exon and one non-coding exon overlapping with NM_000038.6; the 15 coding exons are the same). For the promoter 1B deletion the preferred transcript is NM_001127511.3, which has an alternative coding exon 1. The LRG_130 summarizes all three “additional” exons of the previously mentioned transcripts, resulting in 18 exons). To standardize, variants in this document are described in HGVS nomenclature according to their positions in the NM_000038.6 transcript unless otherwise specified. Numbered exons in this document refers to exons 1-16 in the NM_000038.6transcript. Refer to Supplementary Table 1 for exon number conversions. It is important to note that these criteria are not developed for low/moderate penetrant variants (e. g. c.3920T>A p.(Ile1307Lys) and c.3949G>C p.(Glu1317Gln)).

Version : 2.1.0 Release Notes :

Correction of some inaccuracies in the Rules for Combining Criteria.
Addition of some relevant instructions out of the supplementary material
Change in Fig. 1A: Update of the possible pathways for “G to non-G changes”
Change in Fig. 1B: Transfer of splice variants c.136-1G>A,C,T; c.136-2A>C,G,T; c.220+1G>A,C,T and c.220+2T>A,C,G from List E to List A and transfer of c.220G>A,C,T from List E to List B based on RNA and phenotype data
Update of the supplementary material file.

InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP

Released

11/24/2023

13:46:56

Rules for APC

Gene: APC (HGNC:583) HGNC Name: APC regulator of WNT signaling pathway Transcripts: NM_000038.6 Disease: familial adenomatous polyposis 1 (MONDO:0021056) Mode of Inheritance: Autosomal dominant inheritance

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. Stand Alone Very Strong Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (Figure 1) [Reference 1]. Modification Type: Gene-specific,Strength Strong Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (Figure 1) [Reference 1]. Modification Type: Gene-specific,Strength Moderate Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (Figure 1) [Reference 1]. Modification Type: Gene-specific,Strength Supporting Null variant in a gene where LOF is a known mechanism of disease. As per modified decision tree (Figure 1) [Reference 1]. Modification Type: Gene-specific,Strength Not Applicable
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong The previously established variant was classified as Pathogenic according to the APC-specific modifications. This criterion can be applied to both missense and splice variants in APC. Missense variants: when the variant under assessment results in the same amino acid change as previously established Pathogenic variant(s). There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1_Moderate. No missense variant has been classified as Pathogenic based on current evidence. Splice variants: when the variant under assessment affects splicing at the same nucleotide as a previously established Pathogenic variant. The splice prediction must be above defined thresholds (see instructions) or similar to the previously established variant by multiple in silico predictors. Modification Type: Gene-specific,Strength Moderate The previously established variant was classified as Likely Pathogenic according to the APC-specific modifications. This criterion can be applied to both missense and splice variants in APC. Missense variants: when the variant under assessment results in the same amino acid change as previously established Likely Pathogenic variant(s). There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other variants leading to the same missense change at these positions meet PS1_Moderate. No missense variant has been classified as Pathogenic based on current evidence. Splice variants: when the variant under assessment affects splicing at the same nucleotide as a previously established Likely Pathogenic variant. The splice prediction must be above defined thresholds (see instructions) or similar to the previously established variant by multiple in silico predictors. Modification Type: Gene-specific,Strength Supporting Instructions: Recommended splice prediction programs: SpliceAI: https://spliceailookup.broadinstitute.org/, MaxEntScan : http://hollywood.mit.edu/burgelab/maxent/Xmaxentscan_scoreseq.html for 5’splice sites and http://hollywood.mit.edu/burgelab/maxent/Xmaxentscan_scoreseq_acc.html for 3’splice sites VarSeak: https://varseak.bio/ For SpliceAI a loss of the native splice site is considered for scores between 0.8 and 1. A gain of a cryptic splice site is considered strong for scores between 0.8 and 1 and as moderate for a score between 0.2 and 0.8. For MaxEntScan predictions a score of >3 is required for credibility of a native site prediction and a threshold of -15% is considered for native splice site loss (Houdayer et al. 2012, PMID 22505045). A score >3 is used as a conservative measure for cryptic site use in the context of native site loss. Not Applicable
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Stand Alone Very Strong ≥ 4 de novo scores. For curation of de novo score see Tables 1 and 2. Modification Type: Gene-specific,Strength Strong 2-3.5 de novo scores. For curation of de novo score see Tables 1 and 2. Modification Type: Gene-specific,Strength Moderate 1-1.5 de novo score. For curation of de novo score see Tables 1 and 2. Modification Type: Gene-specific,Strength Supporting Not Applicable
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. Stand Alone Very Strong RNA assays show a premature stop codon OR inframe skipping of exon 13 or 14 AND the absence of full-length transcript. Modification Type: Gene-specific,Strength Strong RNA assays show a premature stop codon OR inframe skipping of exon 13 or 14 AND < 10% of full-length transcript. Modification Type: Gene-specific,Strength Moderate RNA assays show a premature stop codon AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides OR inframe skipping of exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides OR other inframe skipping AND absent or < 10% full-length transcript. Modification Type: Gene-specific,Strength Supporting RNA assays show inframe skipping of exons other than exon 13 or 14 AND reports of exon deletion/skipping/loss, insertion of intronic nucleotides OR over-expression of an alternative transcript (exons 10, 11 or 15) Protein assays show Increased β-catenin regulated transcription activity and/or decreased binding to β-catenin by surface plasmon resonance (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of APC) [Reference 2]. Modification Type: Gene-specific,Strength Not Applicable
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. Stand Alone Very Strong ≥ 16 phenotype points. For phenotype points curation see Table 1. Modification Type: Gene-specific,Strength Strong 4-15.5 phenotype points. For phenotype points curation see Table 1. Modification Type: Gene-specific,Strength Moderate 2-3.5 phenotype points. For phenotype points curation see Table 1. Modification Type: Gene-specific,Strength Supporting 1-1.5 phenotype point. For phenotype points curation see Table 1. Modification Type: Gene-specific,Strength Not Applicable
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. Stand Alone Very Strong Strong Moderate Supporting Rare in controls, defined by an allele frequency ≤ 0.0003% (0.000003) if the allele count is > 1 OR by an allele frequency < 0.001% (0.00001) if the allele count is ≤ 1. Modification Type: Gene-specific,Strength Instructions: General recommendation: Use the total population from the non-cancer dataset from gnomAD (v2.1.1) Not Applicable
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong Moderate The reported missense variant was determined to be Pathogenic according to the APC-specific modifications. There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5_supporting. No missense variant has been classified as Pathogenic based on current evidence. Grantham´s distance of the variant under assessment must have an equal or higher score than the reported variant [Reference 3]. Modification Type: Gene-specific,Strength Supporting The reported missense variant was determined to be Likely Pathogenic according to the APC-specific modifications. There are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). Other different missense variants at these positions meet PM5_supporting. No missense variant has been classified as Pathogenic based on current evidence. Grantham´s distance of the variant under assessment must have an equal or higher score than the reported variant [Reference 3]. Modification Type: Gene-specific,Strength Not Applicable
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Assumed de novo, but without confirmation of paternity and maternity. Stand Alone Very Strong Strong 2-3.5 de novo scores. For curation of de novo score see Tables 1 and 2. Modification Type: Gene-specific,Strength Moderate 1-1.5 de novo scores. For curation of de novo score see Tables 1 and 2. Modification Type: Gene-specific,Strength Supporting 0.5 de novo scores. For curation of de novo score see Tables 1 and 2. Modification Type: Gene-specific,Strength Instructions: PM6_VeryStrong: ≥ 4 de novo scores. For curation of de novo score see Tables 1 and 2. Not Applicable
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. Stand Alone Very Strong Strong Variant segregates in ≥ 7 meioses in ≥ 2 families. Modification Type: Strength Moderate Variant segregates in 5-6 meioses in ≥ 1 family. Modification Type: Strength Supporting Variant segregates in 3-4 meioses in ≥ 1 family. Modification Type: Strength Instructions: Affected individuals exhibit at least 0.5 point of the phenotype point system (see Table 1), for relatives also ≥ 10 or “multiple” colorectal adenomas are considered as 0.5 point. Only genotype and phenotype positive individuals and obligate carriers with phenotype are counted (note: carriers who have received chemoprevention and may have a milder phenotype can also be counted). Not Applicable
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting Missense variants: Do not use computational prediction models for conservation, evolution, etc. In silico splicing predictors should be used for presumed missense variants to reveal possible splicing effects. Non-canonical splicing variants: Multiple in silico splicing predictors support a deleterious effect. Modification Type: Gene-specific,Strength Instructions: Recommended splice prediction programs: see PS1 Not Applicable
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
PP5
Original ACMG Summary Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Stand Alone GnomAD Popmax Filtering Allele Frequency (AF) ≥ 0.1% (0.001). Modification Type: Gene-specific Very Strong Strong Moderate Supporting Instructions: General recommendation: Use the non-cancer dataset from gnomAD (v2.1.1) Not Applicable
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is greater than expected for disorder. Stand Alone Very Strong Strong GnomAD Popmax Filtering Allele Frequency (AF) ≥ 0.001% (0.00001). Modification Type: Gene-specific Moderate Supporting Instructions: General recommendation: Use the non-cancer dataset from gnomAD (v2.1.1) Not Applicable
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. Stand Alone Very Strong Strong ≥ 10 points for healthy individuals OR ≥ 2 times in homozygous state. A healthy individual worth 1 point is defined by: Age ≥ 50 years + Less than 5 adenomatous polyps in a colonoscopy + Absence of features in Table 1 OR Age ≥ 50 years + Colorectal cancer/polyposis was not the indication for testing A healthy individual worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population. Modification Type: Gene-specific,Strength Moderate Supporting ≥ 3 points for healthy individuals. A healthy individual worth 1 point is defined by: Age ≥ 50 years + Less than 5 adenomatous polyps in a colonoscopy + Absence of features in Table 1 OR Age ≥ 50 years + Colorectal cancer/polyposis was not the indication for testing A healthy individual worth 0.5 points is defined by keywords including control, non-cancer, normal, unaffected population. Modification Type: Gene-specific,Strength Instructions: The non-cancer dataset from gnomAD (v2.1.1) cannot be used for ”heterozygous healthy individuals”, because of the limited phenotype information and since it is usually already used for BA1/BS1. However, the non-cancer dataset from gnomAD (v2.1.1) can be used to search for homozygous individuals. Not Applicable
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Stand Alone Very Strong Strong RNA assay of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration AND biallelic expression is shown and/or nonsense-mediated decay inhibition was used. Modification Type: Gene-specific,Strength Moderate Supporting RNA assay of a synonymous or intronic variant in constitutional patient sample demonstrates no mRNA aberration, without demonstration of biallelic expression or use of nonsense-mediated decay inhibition OR Protein assay show retention of β-catenin regulated transcription activity comparable to wild-type (only for variants within the β-catenin binding domain, which refers to codons 959-2129 of APC, see PMID: 33348689) Modification Type: Gene-specific,Strength Not Applicable
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. Stand Alone Very Strong Strong Affected member without the variant must score at least 1 phenotype point or at least two affected members without the variant must each score at least 0.5 phenotype points (see Table 1). Modification Type: Gene-specific,Strength Moderate Supporting Affected member without the variant must score at least 0.5 phenotype points (see Table 1). Modification Type: Gene-specific,Strength Not Applicable
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene for which primarily truncating variants are known to cause disease. Stand Alone Very Strong Strong Moderate Supporting BP1 is applicable to APC with the exception of missense variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035). Modification Type: No change Instructions: A number of assumed “missense” variants are in fact splice variants. At least several splice prediction tools should be used. Recommended splice prediction programs: see PS1 Not Applicable
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. Stand Alone Very Strong Strong Moderate Supporting Observed in trans with a (Likely) Pathogenic APC variant OR ≥ 3 times in an unknown phase with different (Likely) Pathogenic APC variants. Modification Type: Gene-specific Not Applicable
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary In frame-deletions/insertions in a repetitive region without a known function. Stand Alone Very Strong Strong Moderate Supporting Not Applicable
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting Missense variants: BP4 is not applicable. Synonymous (silent) or intronic variants: Multiple in silico splicing predictors suggest no impact on gene or gene product. Modification Type: Gene-specific Instructions: Recommended splice prediction programs: see PS1 Not Applicable
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Variant found in a case with an alternate molecular basis for disease. Stand Alone Very Strong Strong Moderate Supporting Only applicable for an alternate genetic basis of the colorectal polyposis phenotype. Modification Type: No change Instructions: (Likely) Pathogenic variant in another adenomatous polyposis gene (heterozygous variants in POLD1 or POLE; biallelic variants in MUTYH, NTHL1 or MSH3; in patients with onset in childhood / adolescence: biallelic variants in MLH1, MSH2, MSH6 or PMS2). This rule is only applicable when a colorectal polyposis phenotype is present. Not Applicable
BP6
Original ACMG Summary Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Stand Alone Very Strong Strong Moderate Supporting A synonymous (silent) or intronic variant at or beyond +7/–21 for which multiple splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site. Modification Type: General recommendation Instructions: The use of BP7 with BP4 is allowed. Recommended splice prediction programs: see PS1 Not Applicable

Rules for Combining Criteria

Pathogenic

≥ 2 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM6_Strong, PP1_Strong)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM6_Strong, PP1_Strong) AND ≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM5, PM6, PP1_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM6_Strong, PP1_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM5, PM6, PP1_Moderate) AND ≥ 2 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM6_Strong, PP1_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM5, PM6, PP1_Moderate) AND ≥ 4 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3)

1 Very Strong (PVS1) AND ≥ 1 Strong (PS1, PS2, PS4, PM6_Strong, PP1_Strong)

1 Very Strong (PS2_Very Strong, PS3_Very Strong, PS4_Very Strong) AND ≥ 1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM6_Strong, PP1_Strong)

1 Very Strong (PVS1) AND ≥ 2 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM5, PM6, PP1_Moderate)

1 Very Strong (PS2_Very Strong, PS3_Very Strong, PS4_Very Strong) AND ≥ 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM5, PM6, PP1_Moderate)

1 Very Strong (PVS1) AND 1 Moderate (PS1_Moderate, PS2_Moderate, PS4_Moderate, PM5, PM6, PP1_Moderate) AND 1 Supporting (PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1)

1 Very Strong (PS2_Very Strong, PS3_Very Strong, PS4_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM5, PM6, PP1_Moderate) AND 1 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3)

1 Very Strong (PVS1) AND ≥ 2 Supporting (PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1)

1 Very Strong (PS2_Very Strong, PS3_Very Strong, PS4_Very Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3)

Likely Pathogenic

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM6_Strong, PP1_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM5, PM6, PP1_Moderate)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM6_Strong, PP1_Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3)

≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM5, PM6, PP1_Moderate)

2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM5, PM6, PP1_Moderate) AND ≥ 2 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3)

1 Strong (PVS1_Strong, PS1, PS2, PS3, PS4, PM6_Strong, PP1_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM5, PM6, PP1_Moderate)

1 Very Strong (PVS1) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS4_Moderate, PM5, PM6, PP1_Moderate)

1 Very Strong (PS2_Very Strong, PS3_Very Strong, PS4_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM5, PM6, PP1_Moderate)

1 Very Strong (PVS1) AND 1 Supporting (PVS1_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1)

1 Very Strong (PS2_Very Strong, PS3_Very Strong, PS4_Very Strong) AND 1 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3)

1 Moderate (PVS1_Moderate, PS1_Moderate, PS2_Moderate, PS3_Moderate, PS4_Moderate, PM5, PM6, PP1_Moderate) AND ≥ 4 Supporting (PVS1_Supporting, PS3_Supporting, PS4_Supporting, PM2_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3)

Benign

1 Stand Alone (BA1)

≥ 2 Strong (BS1, BS2, BS3, BS4)

Likely Benign

≥ 2 Supporting (BS2_Supporting, BS3_Supporting, BS4_Supporting, BP1, BP2, BP4, BP5, BP7)

1 Strong (BS1, BS2, BS3, BS4)

Files & Images

Supplementary material_V2:

APC-specifi c rules for combining criteria:

Fig. 1: Modified decision tree for PVS1_Variable [Reference 1]

Table 1&2: Table 1. Point system for phenotypic description relevant to criteria PS2, PS4, PM6, PP1 and BS4 & Table 2. Curation of de novo score for PS2 / PM6 based on the phenotype point system

References

1. Abou Tayoun AN Pesaran T et al. Recommendations for interpreting the loss of function PVS1 ACMG/AMP variant criterion. Hum Mutat (2018) 39 (11) p. 1517-1524. 10.1002/humu.23626 30192042

2. Juanes MA Cytoskeletal Control and Wnt Signaling-APC's Dual Contributions in Stem Cell Division and Colorectal Cancer. Cancers (Basel) (2020) 12 (12) 10.3390/cancers12123811 33348689

3. Grantham R Amino acid difference formula to help explain protein evolution. Science (1974) 185 (4154) p. 862-4. 10.1126/science.185.4154.862 4843792