Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000051.3(ATM):c.7271T>G (p.Val2424Gly)

Curation Version - 1.1
Curation History
JSON LD for Version 1.1

CA115930

3023 (ClinVar)

Gene: ATM

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 36ae7580-8da9-4ce9-9040-32e7eee1bb34

Approved on: 2022-03-09

Published on: 2022-07-11

HGVS expressions

NM_000051.3:c.7271T>G

NM_000051.3(ATM):c.7271T>G (p.Val2424Gly)

NC_000011.10:g.108329202T>G

CM000673.2:g.108329202T>G

NC_000011.9:g.108199929T>G

CM000673.1:g.108199929T>G

NC_000011.8:g.107705139T>G

NG_009830.1:g.111371T>G

NG_054724.1:g.145631A>C

ENST00000278616.9:c.7271T>G

ENST00000525056.2:n.1690T>G

ENST00000525537.3:n.228T>G

ENST00000638786.2:n.108T>G

ENST00000682286.1:n.2028T>G

ENST00000682302.1:n.1689T>G

ENST00000683174.1:n.8755T>G

ENST00000683524.1:n.2495T>G

ENST00000684152.1:n.2985T>G

ENST00000684447.1:n.1734T>G

ENST00000527805.6:c.*2335T>G

ENST00000675595.1:c.*2406T>G

ENST00000675843.1:c.7271T>G

ENST00000278616.8:c.7271T>G

ENST00000452508.6:c.7271T>G

ENST00000524792.5:n.3486T>G

ENST00000525537.2:n.547T>G

ENST00000525729.5:c.641-20131A>C

ENST00000527389.2:n.296T>G

ENST00000533690.5:n.2675T>G

NM_001330368.1:c.641-20131A>C

NM_001351110.1:c.*38+6018A>C

NM_001351834.1:c.7271T>G

NM_001330368.2:c.641-20131A>C

NM_001351110.2:c.*38+6018A>C

NM_001351834.2:c.7271T>G

NM_000051.4:c.7271T>G

NM_000051.4(ATM):c.7271T>G (p.Val2424Gly)

Pathogenic

PS4 PP1 PP3 PM3_Very Strong PS3_Moderate

PM2 PP4

Evidence Links 0

Expert Panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

Criteria Specification Information

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

PDF

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

The ATM c.7271T>G (p.Val2424Gly) variant has a GnomAD (v2.1.1) allele frequency of 0.004124% (NFE) which is above the PM2 threshold of .001% but below the BS1 threshold of .05%. This variant is predicted deleterious by multiple protein in silico tools (PP3). This variant is non-functional in multiple different protein assays (PMIDs:19431188,18634022) (PS3_Moderate). The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls in a case control study with lower CI ≥1.5 (PMIDs: 16958054, 21787400) (PS4). This variant has been observed in a homozygous and/or compound heterozygous state (presumed and/or confirmed) in multiple individuals with ataxia-telangiectasia (GeneDx, PMIDs: 9463314, 18575927, 27528516) (>8 points - PM3_Very strong). This variant co-segregated with ataxia-telangiectasia in multiple affected family members (PMID: 18575927) (PP1). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.

PS4

Case Control Study with lower CI ≥1.5 (16958054, 21787400)

PP1

This variant co-segregated with ataxia telangiectasia in multiple affected family members (PMID: 18575927) (PP1).

PP3

This variant is predicted deleterious by multiple protein in silico tools (PP3)

PM3_Very Strong

This variant has been observed in a homozygous and/or compound heterozygous state (presumed and/or confirmed) in multiple individuals with Ataxia-Telangiectasia (GeneDx, PMIDs: 9463314, 18575927, 27528516) (18)

PS3_Moderate

Non-functional in multiple different protein assays (PMIDs:19431188,18634022)

PM2

This variant has a GnomAD (v2.1.1) allele frequency of 0.004124% (NFE) which is above the PM2 threshold of .001% but below the BS1 threshold of .05%.

PP4

Mother (HET) and 3 affected siblings (HOM) show normal size and levels of ATM protein (PMID 9463314)

Curation History

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