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 1.3.0

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

Version : 1.3.0 Release Notes :

Release notes v1.3
Clarified application of BP4 + BP7_Variant(RNA) verbiage in CSPEC editor and rules document:
BP7 _Variable(RNA): RNA functional studies
Lack of aberrant splice defect: Please see PVS1(RNA) section (above) for guidance on baseline weights and modifications of weight based on quality for RNA assays
NOTE: BP4 splice predictions may not be used in conjunction with BP7_Variable(RNA)

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

Released

3/27/2024

17:12:46

Rules for ATM

Release notes v1.3 Clarified application of BP4 + BP7_Variant(RNA) verbiage in CSPEC editor and rules document: BP7 _Variable(RNA): RNA functional studies Lack of aberrant splice defect: Please see PVS1(RNA) section (above) for guidance on baseline weights and modifications of weight based on quality for RNA assays NOTE: BP4 splice predictions may not be used in conjunction with BP7_Variable(RNA)

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 inheritance ataxia telangiectasia (MONDO:0008840) Mode of Inheritance: Autosomal recessive inheritance ataxia - telangiectasia variant (MONDO:0018266) Mode of Inheritance: Autosomal recessive 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 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. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect. Modification Type: General recommendation Moderate Use for protein changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect. Modification Type: General recommendation,Strength Supporting Instructions: Use as ascribed for protein changes as long as a splice defect is ruled out for both variants; Use Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect. (PMID: 36865205) 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_Strength(RNA) 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 Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5). Modification Type: General recommendation Moderate Do not use for proband counting. Modification Type: Disease-specific,Gene-specific Supporting Instructions: Do not use for 'proband counting' method. Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR 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% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2_supporting would not apply Modification Type: Gene-specific,Strength Instructions: Frequency ≤.001% if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply. n>1 in one or multiple subpopulations would not be considered rare and PM2_supporting would not apply 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: Disease-specific,General recommendation,Gene-specific,Strength Strong Use ATM PM3/BP2 table. Modification Type: Disease-specific,General recommendation,Gene-specific,Strength Moderate Use ATM PM3/BP2 table. Modification Type: Disease-specific,General recommendation,Gene-specific,Strength Supporting Use ATM PM3/BP2 table Modification Type: Disease-specific,General recommendation,Gene-specific,Strength 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: General recommendation,Gene-specific 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. Apply also to splice variants as PM5_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Arg3047 where PVS1_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone. Do not use for start-loss variants Modification Type: Gene-specific,Strength Instructions: Use for genomic frameshift and truncating variants with PTC upstream of p.R3047. Apply also to splice variants as PM5_supporting for splice variants can only be applied for variants premature termination codons upstream of p.Arg3047 where PVS1_VS(RNA) is applied based on high quality observed splicing impact and must be NMD prone. Do not use for start-loss variants 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 Comments: Do not use: ATM does not have a defined low rate of missense benign variation.
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: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing Modification Type: Gene-specific Instructions: Protein: REVEL >.7333 RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) NOTE: PP3 for splice predictions may not be applied in addition to PVS1 or PVS1_Variable(RNA) codes. Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism. 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%. Modification Type: Disease-specific 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%. Modification Type: Disease-specific 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: Disease-specific,Gene-specific,Strength Supporting Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity. Modification Type: Disease-specific,Gene-specific,Strength Instructions: For protein, see detailed notes on ATM-specific assays; For RNA use code BP7_RNA 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 Comments: AD Condition: Co-segregation analysis in lowpenetrance genes can lead to false positive results (PMID 32773770) . AR Condition: informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family.
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: Disease-specific,General recommendation,Gene-specific,Strength Moderate Use ATM PM3/BP2 table. Modification Type: Disease-specific,General recommendation,Gene-specific,Strength Supporting Use ATM PM3/BP2 table Modification Type: Disease-specific,General recommendation,Gene-specific,Strength 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 Protein Analysis: Metapredictor REVEL score ≤.249 RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing NOTE: Splice analysis needs to be considered for all variant types (including missense, frameshift, nonsense, etc. as any variant has the potential to impact splicing which may preclude any expected protein effects) NOTE: BP4 for splice predictions may not be applied in conjunction with BP7_Variable(RNA) (a lack of observed RNA defect) Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism. Modification Type: General recommendation 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_(RNA) with curator discretion of quality. Modification Type: General recommendation Moderate Can be considered for BP7_(RNA) with curator discretion of quality. Modification Type: General recommendation Supporting Can be considered for BP7_(RNA) 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: BP7: Synonymous and deep intronic Can be used for deep intronic variants beyond (but not including) +7 (donor) and -40 (acceptor) May also apply BP4 to achieve Likely Benign Is not considered a conflicting piece of evidence against a body of evidence supporting a pathogenic splice defect BP7 _Variable(RNA): RNA functional studies Lack of aberrant splice defect: Please see PVS1(RNA) section (above) for guidance on baseline weights and modifications of weight based on quality for RNA assays NOTE: BP4 splice predictions may not be used in conjunction with BP7_Variable(RNA) 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.

Rules for Combining Criteria

Pathogenic

1 Very Strong (PVS1, PM3_Very Strong) AND ≥ 1 Strong (PVS1_Strong, PS1, PS3, PS4, PM3_Strong)

1 Very Strong (PVS1, PM3_Very Strong) AND ≥ 2 Moderate (PVS1_Moderate, PS1_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4)

1 Very Strong (PVS1, PM3_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4) AND 1 Supporting (PVS1_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP3)

1 Very Strong (PVS1, PM3_Very Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP3)

≥ 2 Strong (PVS1_Strong, PS1, PS3, PS4, PM3_Strong)

1 Strong (PVS1_Strong, PS1, PS3, PS4, PM3_Strong) AND ≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4)

1 Strong (PVS1_Strong, PS1, PS3, PS4, PM3_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4) AND ≥ 2 Supporting (PVS1_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP3)

1 Strong (PVS1_Strong, PS1, PS3, PS4, PM3_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4) AND ≥ 4 Supporting (PVS1_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP3)

Likely Pathogenic

1 Very Strong (PVS1, PM3_Very Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4)

1 Strong (PVS1_Strong, PS1, PS3, PS4, PM3_Strong) AND 1 Moderate (PVS1_Moderate, PS1_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4)

1 Strong (PVS1_Strong, PS1, PS3, PS4, PM3_Strong) AND ≥ 2 Supporting (PVS1_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP3)

≥ 3 Moderate (PVS1_Moderate, PS1_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4)

2 Moderate (PVS1_Moderate, PS1_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4) AND ≥ 2 Supporting (PVS1_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP3)

1 Moderate (PVS1_Moderate, PS1_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4) AND ≥ 4 Supporting (PVS1_Supporting, PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP3)

1 Strong (PVS1_Strong, PS1, PS3, PS4, PM3_Strong) AND 2 Moderate (PVS1_Moderate, PS1_Moderate, PS3_Moderate, PS4_Moderate, PM3, PM4)

1 Very Strong (PVS1, PM3_Very Strong) AND 1 Supporting (PS3_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PP3)

Benign

≥ 2 Strong (BS1, BP2_Strong, BP7_Strong)

Likely Benign

1 Strong (BS1, BP2_Strong, BP7_Strong) AND 1 Supporting (BS3_Supporting, BP2, BP4, BP7)

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

1 Strong (BS1, BP2_Strong, BP7_Strong)

Files & Images

ClinGen HBOP ACMG Specifications ATM version 1.3:

ATM supplementary Tables 1 and 2 :