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 Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.1

Description : ACMG-modified rules specifications for ATM (autosomal dominant and autosomal recessive disorders)

Version : 1.1.0 Release Notes :

Corrected combining rules for LP to include PVS1 + PM2_Supporting = LP

PDF

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

Released

2/25/2022

06:00:00

Rules for ATM

Gene: ATM (HGNC:795) HGNC Name: ATM serine/threonine kinase Transcripts: NM_000051.3 Disease: hereditary breast carcinoma (MONDO:0016419) Mode of Inheritance: Autosomal Dominant ataxia telangiectasia (MONDO:0008840) Mode of Inheritance: Autosomal Dominant ataxia - telangiectasia variant (MONDO:0018266) Mode of Inheritance: Autosomal Dominant

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 Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength Strong Use ATM PVS1 Decision Tree. Modification Type: Gene-specific,Strength Moderate Use ATM PVS1 Decision Tree. Modification Type: Gene-specific,Strength Supporting Use ATM PVS1 Decision Tree Modification Type: Gene-specific,Strength Instructions: Use ATM PVS1 Decision Tree. Not Applicable Comments: Used with PM5_Supporting for non-splice, non-start-loss LoF variants with PTCs upsteram of p.R3047. Per points system, PVS1 + 1 Supporting = LP.
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 Use for protein changes as long as splicing is ruled-out for both alterations. Modification Type: General recommendation Moderate Use for RNA changes as code PS1_RNA_Moderate if predictions or observations are similar or worse for the variant under consideration. Close matches must be VCEP approved LP/P variants. Modification Type: Strength,General recommendation Supporting Instructions: Use as ascribed for protein changes as long as a splice defect is ruled out for both variants; Use as PS1_RNA_Moderate for close-match splicing variants with similar predictions or observations of splice defect. Close matches must be VCEP approved as LP/P. 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 Strong Moderate 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 Strong Do not use as strong. Modification Type: Gene-specific Moderate Use when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity. Modification Type: Gene-specific,Strength Supporting Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency Modification Type: Gene-specific,Strength Instructions: For protein, see detailed notes on ATM-specific assays; For RNA use code PVS1_O and modulate strength based on assay quality and quantity (curator discretion). Not Applicable Comments: Conflicting functional studies should not be given any weight.
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 Use for case control studies that reflect an OR ≥2, p≤.05 and lower 95% CI ≥1.5. Modification Type: General recommendation Moderate Do not use for proband counting. Modification Type: Gene-specific,Disease-specific Supporting Instructions: Do not use for 'proband counting' method. Use for case control studies that reflect an OR ≥2, p≤.05 and lower 95% CI ≥1.5. 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 Frequency ≤.001% when N>1 in a large general population database (e.g. gnomAD 2.1.1) Modification Type: Gene-specific,Strength Instructions: Use as PM2_Supporting for variants with a general population frequency ≤.001% in all sub-populations when N>1. Not Applicable Comments: PM2_Supporting is not considered a conflicting piece of evidence to an otherwise benign body of evidence; Coverage must be >30X at the locus.
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 Use ATM PM3/BP2 table. Modification Type: Gene-specific,Disease-specific,Strength,General recommendation Strong Use ATM PM3/BP2 table. Modification Type: Gene-specific,Disease-specific,Strength,General recommendation Moderate Use ATM PM3/BP2 table. Modification Type: Gene-specific,Disease-specific,Strength,General recommendation Supporting Use ATM PM3/BP2 table Modification Type: Gene-specific,Disease-specific,Strength,General recommendation Instructions: Use ATM PM3/BP2 table. Not Applicable Comments: Multiple such cases are additive, Phenotype considerations are detailed in the rules, frequency of >.01% should not use PM3; Observations in cis are not applicable. Source information is considered (laboratory vs database setting).
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 Use for stop-loss variants. Modification Type: Gene-specific,General recommendation Supporting Instructions: Do not use for in-frame insertions or deletions less than a single exon; Use for stop-loss variants, only. 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 Supporting Use for genomic frameshift and truncating variants with PTC upstream of p.R3047. Do not use for splice or start-loss variants Modification Type: Gene-specific,Strength Instructions: Do not use for 'hotspot'. Can be used for genomic frameshift and truncating variants with PTC upstream of p.R3047 as PM5_Supporting. Not Applicable Comments: No rescue splicing isoforms have been identified in ATM.
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
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 Moderate Supporting Not Applicable Comments: Informative pedigrees for segregation in families with AR Ataxia-Telangiectasia are not available. However, this VCEP would consider rules similar to the Glanzman and Hearing Loss VCEP rules if a pedigree becomes available.
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 Protein: REVEL >.7333; RNA: multiple in silico predictors agree to a smilar effect Instructions: Protein: REVEL >.7333; RNA: multiple in silico predictors agree to a similar effect. Not Applicable Comments: Check splicing scores for all variant types. Do not combine splice prediction weight with other lines of protein evidence.
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 Filtering Allele Frequency >.5%. Very Strong Strong Moderate Supporting Instructions: Filtering Allele Frequency >.5%. Not Applicable Comments: FAF is a statistical model that accounts for population size and founder populations.
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 Filtering Allele Frequency >.05%. Moderate Supporting Instructions: Filtering Allele Frequency >.05%. Not Applicable Comments: FAF is a statistical model that accounts for population size and founder populations.
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 Moderate Supporting 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 Moderate Use when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity. Modification Type: Gene-specific,Disease-specific,Strength,General Recommendation Supporting Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity. Modification Type: Gene-specific,Disease-specific,Strength,General Recommendation Instructions: For protein, see detailed notes on ATM-specific assays; For RNA use code BP7_O and modulate strength based on assay quality and quantity (curator discretion). 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 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
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 Use ATM PM3/BP2 table. Modification Type: Gene-specific,Disease-specific,Strength,General recommendation Moderate Use ATM PM3/BP2 table. Modification Type: Gene-specific,Disease-specific,Strength,General recommendation Supporting Use ATM PM3/BP2 table Modification Type: Gene-specific,Disease-specific,Strength,General recommendation Instructions: Use ATM PM3/BP2 table. Not Applicable Comments: Multiple such cases are additive, age considerations (>18yo) are required. Observations in cis are not applicable. Source information is considered (laboratory vs database setting).
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 Instructions: Protein: REVEL <.249; RNA: multiple in silico predictors agree to a lack of splice defect. 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
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 Can be considered for BP7_O with curator discretion of quality. Modification Type: General recommendation Moderate Can be considered for BP7_O with curator discretion of quality. Modification Type: General recommendation Supporting Can be considered for BP7_O with curator discretion of quality; Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively Modification Type: General recommendation Instructions: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -40 at donor and acceptor sites, respectively. Use as BP7_O for synonymous and intronic variants with no splice defect observed. Weight for BP7_O is variable based on curator impression fo assay quality (not specified). Not Applicable Comments: BP4 may be used in addition to BP7 for sysnonymous and deep intronic variants to achieve LB; BP7 is not a conflicting piece of evidence against an otherwise pathogenic body of evidence; BP7_O should NOT be used in conjunction with BP4.