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.

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Criteria Specification

ClinGen DICER1 and miRNA-Processing Gene Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for DICER1 Version 1.2.0

Version : 1.2.0 Release Notes :

Added clarifying language for use of splice predictors for variants outside of MES prediction range (PS1, PM5, PP3, BP4).
Tweaked language to clarify meaning of caveat in Evidence Criteria Combinations Bayesian Points table.
Cleaned up appearance in C Spec (e.g., utilizing "Instructions" boxes for repeated text; activating in-text citations and reference list). No text changes were made in these situations.
Updated MONDO ID from the OLS3 MONDO:0017288 "DICER1 syndrome" to the newly named OLS4 ID MONDO:0100216 "DICER1-related tumor predisposition". This update was made by MONDO at the request of ClinGen to align with the dyadic naming system for genetic conditions.

DICER1 and miRNA-Processing Gene VCEP

Released

5/31/2023

20:35:31

Rules for DICER1

Gene: DICER1 (HGNC:17098) HGNC Name: dicer 1, ribonuclease III Transcripts: NM_177438.2 Disease: DICER1-related tumor predisposition (MONDO:0100216) 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 Follow SVI guidance, using DICER1-specific information. Per the PVS1 workflow guidance provided in Tayoun et al. 2018¹, the following will apply: Nonsense or frameshift variants: PVS1 applies to variants predicted to result in nonsense-mediated decay (NMD); the predicted NMD cutoff for DICER1 occurs at p.Pro1850. PVS1_Moderate applies to variants resulting in protein truncation 3’ of this cutoff Canonical splice variants (+/- 1,2 intronic positions): PVS1 applies with the following exceptions: Exon 10 SDS/SAS: PVS1_Strong (in-frame but exon includes >10% protein) Exons 5, 15, 18, 22 SDS/SAS: PVS1_Moderate (in-frame and each <10% of protein) Exon 27 SAS: PVS1_Moderate (final exon) Exon 1: no criteria (non-coding) Variants that disrupt the translation start site (p.M1?): no criteria applied given p.M1 is not highly conserved, there are three in-frame possible alternate start codons (p.Met11, p.Met17, p.Met24), and multiple lab cases of p.Met1? without DICER1 phenotype. SDS = splice donor site; SAS = splice acceptor site. Refer to PS3 weight guidelines when a variant meets criterion for application of both PVS1 and PS3. A disease-specific PVS1 decision tree incorporating the above bullets is also included at the end of this document as an additional curation tool. Modification Type: Disease-specific,General recommendation Strong Moderate Supporting 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 For same AA change, must confirm there is no difference in splicing using RNA data or in-silico modeling data (concordance of MaxEntScan and SpliceAI). For non-canonical intronic splicing variants at same nucleotide should have equal or worse splicing impact. This rule code can only be used to compare variants asserted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply. Modification Type: General recommendation Moderate Supporting Instructions: All variants should be assessed by MaxEntScan (MES) and SpliceAI for predicting de novo and cryptic splice sites. However, for predicting impact to consensus splice sites, SpliceAI scores alone should be considered for variants outside the MES validation threshold, as MES is not capable of predicting native splice site impact for such variants. (MES validation threshold = last 3 nucleotides of exon through intronic position +6 (donor sites); intronic position -20 through first 3 nucleotides of exon (acceptor sites)) 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 points Modification Type: Strength Strong ≥2 but less than 4 de novo points Modification Type: Strength Moderate ≥1 but less than 2 de novo points Modification Type: General recommendation Supporting ≥0.5 but less than 1 de novo points Modification Type: Strength Instructions: De novo points should be tallied using the simplified table for tallying proband points and used to determine the applied strength of PS2, consistent with SVI guidance. To avoid redundancy and increase consistency, the EP has opted to drop PM6 and exclusively use PS2 for de novo evidence. 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 Strong RNA assay shows splicing impact that is out-of-frame, in-frame ≥193 residues, or in-frame with RNase IIIb disruption. (PS3_Moderate if PVS1_Strong is applied). Modification Type: Disease-specific Moderate RNA assay shows in-frame splicing impact with change in protein length <193 residues AND RNase IIIb domain not disrupted. Modification Type: Disease-specific,General recommendation Supporting In vitro cleavage assay shows failure or severely reduced capacity to produce either 5p or 3p microRNAs from a premiRNA (positive and negative controls also performed). Modification Type: Disease-specific,Strength Instructions: This rule should be used and weighted appropriately for variants with functional evidence of a splicing impact and/or reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies. Do not apply PS3 at any strength if PVS1 is applied at full 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 Strong ≥4 phenotype points Modification Type: General recommendation Moderate 2 – 3.5 phenotype points Modification Type: Strength Supporting 1 – 1.5 phenotype points Modification Type: Strength Instructions: Unrelated probands may contribute up to 1 point each based on phenotype (see Tables 2 & 3 in ruleset) Caveats: Do not apply PS4 if variant meets BA1/BS1 criteria. Do not apply points for a phenotype in an individual with a likely pathogenic germline variant in a second gene that could have reasonably contributed to the phenotype (e.g. Wilms tumor in an individual with a P/LP WT1 variant). Do not apply points for a proband whose tumor sequencing is consistent with a likely sporadic event (i.e. sequencing reveals a somatic, VCEPcurated, non-hotspot, likely pathogenic DICER1 variant in addition to a somatic hotspot variant and the germline variant under assessment). Of note, DICER1 tumors that consistently or occasionally follow a classical 2- hit hypothesis (i.e. LOF of both alleles) are exempt from this caveat. For example, identification of a somatic pathogenic non-hotspot DICER1 variant in pineoblastoma², pituitary blastoma³, and lung cysts or cystic nephroma lacking mesenchymal cells⁴,⁵ should not exclude the proband from PS4. 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 Putative missense variants at residues affecting metal ion-binding: codons p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, p.E1813 Modification Type: Disease-specific Supporting Putative missense variants at residues in the RNase IIIb domain (p.Y1682 – p.S1846), besides the metal ion-binding residues (see PM1). Modification Type: Strength 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 Allele frequency <0.000005 across gnomAD (non-cancer) with no more than one allele in any subpopulation and at least 20x coverage. Modification Type: Disease-specific,Strength 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 Comments: Autosomal dominant.
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 In-frame indels with a residue within the RNase IIIb domain (p.Y1682 – p.S1846). Modification Type: Disease-specific Supporting In-frame indels outside of the RNase IIIb domain (p.Y1682 – p.S1846) and repeat regions (p.D606-p.D609; p.E1418-p.E1420; p.E1422-p.E1425). Modification Type: Strength 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 Missense variant under evaluation should have equal or worse Grantham score. Splicing should be ruled out with either RNA data or agreement in splicing predictors (MaxEntScan and SpliceAI) that show no splicing effects. The other variant must be interpreted as pathogenic by the ClinGen DICER1 VCEP. Likely pathogenic changes do not apply. This rule cannot be applied in combination with PM1 or PS1. Modification Type: General recommendation Supporting Instructions: All variants should be assessed by MaxEntScan (MES) and SpliceAI for predicting de novo and cryptic splice sites. However, for predicting impact to consensus splice sites, SpliceAI scores alone should be considered for variants outside the MES validation threshold, as MES is not capable of predicting native splice site impact for such variants. (MES validation threshold = last 3 nucleotides of exon through intronic position +6 (donor sites); intronic position -20 through first 3 nucleotides of exon (acceptor sites)) 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 Moderate Supporting Not Applicable Comments: Combined with PS2. Use PS2 instead of PM6.
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 ≥7 meioses across ≥2 families Modification Type: Strength Moderate 5 – 6 meioses across ≥1 family Modification Type: Strength Supporting 3 – 4 meioses across ≥1 family Modification Type: General recommendation Instructions: Phenotype-positive individuals should have high, moderate, or low-specificity phenotypes (see phenotype table). (Caveat: segregation with a single low-specificity phenotype across multiple individuals (e.g. familial Wilms tumor) does not fulfill PP1.) Do not apply PP1 if variant meets BA1/BS1 criteria. 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 Comments: While DICER1 does meet recommended cutoff for missense constraint z score of ≥3.09 established by the SVI (4.23 on gnomAD) the VCEP recommends this rule not be used for DICER1 due to the presence of various missense variants throughout the gene that are clinically interpreted as benign (9) or likely benign (30) in ClinVar.
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 For missense variants, REVEL score ≥ 0.75 OR agreement in splicing predictors predict splicing effects. For splicing variants, concordance of MaxEntScan and SpliceAI. Modification Type: Disease-specific Instructions: All variants should be assessed by MaxEntScan (MES) and SpliceAI for predicting de novo and cryptic splice sites. However, for predicting impact to consensus splice sites, SpliceAI scores alone should be considered for variants outside the MES validation threshold, as MES is not capable of predicting native splice site impact for such variants. (MES validation threshold = last 3 nucleotides of exon through intronic position +6 (donor sites); intronic position -20 through first 3 nucleotides of exon (acceptor sites)) 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 Somatic tumor testing identifies somatic hotspot second hit and no additional somatic LOF variants. Tumor testing⁶ of a neoplasm with known DICER1 association in a proband who carries the germline variant under evaluation reveals the following: A previously reported somatic second hit of DICER1 in an RNase IIIb-disrupting “hotspot” codon (p.S1344, p.E1705, p.D1709, p.D1713, p.G1809, p.D1810, or p.E1813) AND Retention of the germline DICER1 variant under evaluation. PP4 is NOT applicable if: The germline variant is a missense variant in one of the seven RNase IIIb “hotspot” codons (see PM1), OR Somatic sequencing reveals additional DICER1 non-hotspot variants (could be consistent with sporadic tumorigenesis). Modification Type: Disease-specific 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 Frequency >0.003 (0.3%) in gnomAD (non-cancer) subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present. Modification Type: Disease-specific Very Strong Strong Moderate Supporting 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 Frequency >0.0003 (0.03%) in gnomAD (non-cancer) subpopulations. Subpopulations must have >2,000 alleles tested and a minimum of 5 alleles present. Modification Type: Disease-specific Moderate Supporting 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 40+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 40:1) OR 2+ observations of homozygosity in healthy individuals OR 1+ observation(s) of homozygosity in a healthy individual with status confirmed by parental testing. Modification Type: Disease-specific Moderate Supporting 10+ unrelated females from a single source are tumor-free through age 50 (caveat: ratio of BS2-eligible females to PS4-eligible probands must be ≥ 10:1) OR 2+ observations of homozygosity in individuals lacking clinical information Modification Type: Disease-specific 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 For intronic or synonymous variants, no splicing impact observed via RNA assay. (Should be observed more than once.) Modification Type: Disease-specific Moderate Supporting An in vitro cleavage assay must demonstrate the variant produces both 5p and 3p microRNAs from a pre-miRNA (positive and negative controls also performed). An example of an appropriate assay to which criteria could be applied is Wu et al. 2018⁷. Modification Type: Disease-specific Instructions: This rule should be used and weighted appropriately for variants with functional evidence of no splicing impact and/or no reduced DICER1 ability to cleave pre-miRNA. Follow SVI guidance regarding control numbers for functional studies. 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 Family members should be phenotype-positive (must be high- or moderatespecificity phenotype; see phenotype table), genotype-negative 1st, 2nd, or 3rd degree relatives of the proband. Modification Type: General recommendation Moderate Supporting 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 Not Applicable Comments: This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants.
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 ≥1 observation in trans with P/LP DICER1 variant or ≥3 observations in cis or phase unknown with 2+ different P/LP DICER1 variants. Modification Type: Disease-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 Comments: Not applicable at this time.
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 For missense variants, REVEL score < 0.50 and agreement in splicing predictors that no splicing effects are predicted. For synonymous/intronic/non-coding variants concordance of MaxEntScan and SpliceAI. Modification Type: Disease-specific Instructions: All variants should be assessed by MaxEntScan (MES) and SpliceAI for predicting de novo and cryptic splice sites. However, for predicting impact to consensus splice sites, SpliceAI scores alone should be considered for variants outside the MES validation threshold, as MES is not capable of predicting native splice site impact for such variants. (MES validation threshold = last 3 nucleotides of exon through intronic position +6 (donor sites); intronic position -20 through first 3 nucleotides of exon (acceptor sites)) 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 Not Applicable Comments: Given the broad spectrum of DICER1-related neoplasms and the General recommendation lack of evidence of other high-penetrance germline variants that could account for such neoplasms (except perhaps for some already low-specificity phenotypes such as Wilms tumor), this rule should not be used at this time.
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 Silent variant OR Intronic variant at or beyond +7 to -21 positions OR Other intronic or non-coding variant if the variant is the reference nucleotide in ≥1 primate and/or ≥4 mammalian species. Caveat: Variant must meet BP4 to apply BP7 Modification Type: General recommendation Not Applicable

Rules for Combining Criteria

Pathogenic

1 Very Strong (PVS1, PS2_Very Strong) AND ≥ 1 Strong (PS1, PS2, PS3, PS4, PP1_Strong)

1 Very Strong (PVS1, PS2_Very Strong) AND ≥ 2 Moderate (PS2_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate)

1 Very Strong (PVS1, PS2_Very Strong) AND 1 Moderate (PS2_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate) AND 1 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM1_Supporting, PM2_Supporting, PM4_Supporting, PP1, PP3, PP4)

1 Very Strong (PVS1, PS2_Very Strong) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM1_Supporting, PM2_Supporting, PM4_Supporting, PP1, PP3, PP4)

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

1 Strong (PS1, PS2, PS3, PS4, PP1_Strong) AND ≥ 3 Moderate (PS2_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate)

1 Strong (PS1, PS2, PS3, PS4, PP1_Strong) AND 2 Moderate (PS2_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate) AND ≥ 2 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM1_Supporting, PM2_Supporting, PM4_Supporting, PP1, PP3, PP4)

1 Strong (PS1, PS2, PS3, PS4, PP1_Strong) AND 1 Moderate (PS2_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate) AND ≥ 4 Supporting (PS2_Supporting, PS3_Supporting, PS4_Supporting, PM1_Supporting, PM2_Supporting, PM4_Supporting, PP1, PP3, PP4)

Likely Pathogenic

1 Very Strong (PVS1, PS2_Very Strong) AND 1 Moderate (PS2_Moderate, PS3_Moderate, PS4_Moderate, PM1, PM4, PM5, PP1_Moderate)

Benign

≥ 2 Strong (BS1, BS2, BS3, BS4)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS2, BS3, BS4) AND 1 Supporting (BS2_Supporting, BS3_Supporting, BP2, BP4, BP7)

≥ 2 Supporting (BS2_Supporting, BS3_Supporting, BP2, BP4, BP7)

Files & Images

PVS1: Decision Tree Guide for PVS1

Phenotype Table: Phenotypes specificity table for use with PS4, PS2, PP1, PP4, BS4

PP4 Flowchart and Second Hits: Flowchart for application of PP4 and table of qualifying, previously reported somatic second hits.

Table for Tallying Proband Points: Table for tallying points for PS4 and PS2. Use in conjunction with Phenotype Table.

Evidence Criteria Combinations: Modified Bayesian point system for variants with conflicting evidence codes. Adapted from Tables 2 and 3 of Tavtigian et al. 2020 (PMID: 32720330)

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. de Kock L Sabbaghian N et al. Germ-line and somatic DICER1 mutations in pineoblastoma. Acta Neuropathol (2014) 128 (4) p. 583-95. 10.1007/s00401-014-1318-7 25022261

3. de Kock L Sabbaghian N et al. Pituitary blastoma: a pathognomonic feature of germ-line DICER1 mutations. Acta Neuropathol (2014) 128 (1) p. 111-22. 10.1007/s00401-014-1285-z 24839956

4. Wagh PK Gardner MA et al. Cell- and developmental stage-specific Dicer1 ablation in the lung epithelium models cystic pleuropulmonary blastoma. J Pathol (2015) 236 (1) p. 41-52. 10.1002/path.4500 25500911

5. Yin Y Castro AM et al. Fibroblast Growth Factor 9 Regulation by MicroRNAs Controls Lung Development and Links DICER1 Loss to the Pathogenesis of Pleuropulmonary Blastoma. PLoS Genet (2015) 11 (5) p. e1005242. 10.1371/journal.pgen.1005242 25978641

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