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 CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Description : ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2

Version : 2.0.0 Release Notes :

PVS1 applies to initiation codon variants.
Allow a variant to reach a likely benign classification based on BS1 or BS2 alone.
PS3 cannot be applied if the variant meets PVS1. If the variant meets PVS1_strong, we recommend applying PS3_moderate.

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CDH1 VCEP

Released

9/6/2019

05:00:00

Rules for CDH1

Gene: CDH1 (HGNC:1748) HGNC Name: cadherin 1 Transcripts: Disease:

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 Per ClinGen SVI guidelines with the exception of canonical splice sites Apply to initiation codon variant Strong Per ClinGen SVI guidelines Other CDH1 caveats: Use the strong strength of evidence for canonical splice sites CDH1 Exonic deletions or tandem duplications of in-frame exons Truncations in NMD-resistant zone located upstream the most 3’ well-characterized pathogenic variant c.2506G>T (p.Glu836*). Use PVS1_moderate if premature stop is downstream of this variant Moderate Per ClinGen SVI guidelines Other CDH1 caveats: G to non-G variants disrupting the last nucleotide of an exon Canonical splice sites located in exons demonstrated experimentally to result in in-frame partial skipping/insertion (e.g., Exon 3 donor site) Supporting Per ClinGen SVI guidelines Not Applicable Comments: RNA analysis is recommended for splicing alterations, and if the RNA evidence does not support the prediction, the strength should be updated PP3 cannot be applied for canonical splice sites
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 Per original ACMG/AMP guidelines Moderate Supporting Not Applicable Comments: Variant must not impact splicing
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 ≥Two patients with DGC &/or LBC w/ parental confirmation Strong One patient with DGC &/or LBC w/ parental confirmation Moderate Supporting Not Applicable Comments: Use ClinGen’s de novo point system for a highly specific phenotype (see Table S2)
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 demonstrating abnormal out-of-frame transcripts Moderate Supporting RNA assay demonstrating abnormal in-frame transcripts Not Applicable Comments: This rule can only be applied to demonstrate splicing defects. PS3 cannot be applied if the variant meets PVS1. If the variant meets PVS1_strong, we recommend applying PS3_moderate.
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 Sixteen families meet HDGC criteria Strong Four families meet HDGC criteria Moderate Two families meet HDGC criteria Supporting One family meets HDGC criteria Not Applicable Comments: This rule assumes 30% penetrance in individuals with pathogenic variants. For example, if the variant in observed in 3 families, at least one of those families need to meet criteria for HDGC in order to apply this rule. PS4 cannot be applied to variants that meet BS1 or BA1
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 Comments: Do not use for this gene
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 Less than one out of 100,000 alleles in gnomAD cohort; if present in >=2 individuals, must be present in less than one out of 50,000 alleles within a sub-population Supporting Not Applicable Comments: Use gnomAD to determine allele frequency. Beware of technical limitations that can inaccurately represent allele frequency in this population database
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: Does not apply to this gene
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 Per original ACMG/AMP guidelines Supporting Not Applicable Comments: No rule specification proposed. Variant example - CDH1 c.2647T>C (p.Ter883Glnext*29)
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 Supporting Not Applicable Comments: Do not use rule at this time
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 ≥Four patients with DGC &/or LBC w/o parental confirmation Strong ≥Two patients with DGC &/or LBC w/o parental confirmation Moderate One patient with DGC &/or LBC w/o parental confirmation Supporting Not Applicable Comments: Use ClinGen’s de novo point system for a highly specific phenotype (See Table S2)
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 ≥Seven meioses across ≥2 families Moderate Five-six meioses across ≥1 families Supporting Three-four meioses across ≥1 families Not Applicable Comments: Based strength of rule code on number of meioses across one or more families
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 Variants affecting the same splice site as a well-characterized variant with similar or worse in silico/ RNA predictions Supporting At least three in silico splicing predictors in agreement (.Human Splicing Finder (HSF), Maximum Entropy (MaxEnt), Berkeley Drosophilia Genome Project (BDGP), or ESEfinder) Not Applicable Comments: Rule code is only for non-canonical splicing variants. Code also does not apply to last nucleotide of exon 3 (c.387G). Do not use protein-based computational prediction models for missense variants
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 MAF cutoff of 0.2% Very Strong Strong Moderate Supporting Not Applicable Comments: 99.99% CI; subpopulation must have a minimum of five alleles present
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 MAF cutoff of 0.1% Very Strong Strong Moderate Supporting Not Applicable Comments: 99.99% CI; subpopulation must have a minimum of five alleles present We allow a variant to reach a likely benign classification based on BS1 alone
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 Variant seen in ≥10 individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC Moderate Supporting Variant seen in ≥3 individuals w/o DCG, SRC tumors, or LBC & whose families do not suggest HDGC Not Applicable Comments: We allow a variant to reach a likely benign classification based on BS2 alone
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 Functional RNA studies demonstrating no impact on transcript composition Moderate Supporting Not Applicable Comments: This rule can only be used to demonstrate lack of splicing and can be downgraded based on quality of data
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 Per original ACMG/AMP guidelines Moderate Supporting Not Applicable Comments: Beware of the presence of phenocopies (e.g., breast cancer) that can mimic lack of segregation. Also, families may have more than one pathogenic variant contributing to another AD disorder
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
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 Variant observed in trans w/known pathogenic variant (phase confirmed) OR observed in the homozygous state in individual w/o personal &/or family history of DGC, LBC, or SRC tumors Moderate Supporting Variant is observed in cis (or phase is unknown) w/ a pathogenic variant Not Applicable Comments: Evidence code is dependent on strength of data. Take consideration of quality of sequencing data when applying code. Note that code requires knowledge of individuals’ phenotype. Therefore, data from population databases should only be used when phenotypic info is available
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 Splicing predictions only. At least three in silico splicing predictors in agreement (Human Splicing Finder (HSF), Maximum Entropy (MaxEnt), Berkeley Drosophilia Genome Project (BDGP), or ESEfinder) Not Applicable Comments: This rule can only be used when splicing predictions models suggest no impact on protein. Do not use protein based computational prediction models for missense. variants
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 Per original ACMG/AMP guidelines Not Applicable Comments: This applies if a P/LP variant is identified in an alternate gene known to cause HDGC (e.g., CTNNA1)
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 Synonymous variants where nucleotide is not highly conserved; variant is the reference nucleotide in one primate and/or >3 mammal species Not Applicable Comments: Note the CDH1 rule specification does not require a benign in silico splice prediction. This allows use with BP4, as appropriate, to classify variants meeting both criteria as likely benign