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

CA115930

3023 (ClinVar)

Gene: ATM

Condition: hereditary breast cancer

Inheritance Mode: Autosomal dominant inheritance

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

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

• Met criteria codes: PM3_Very Strong PS4 PS3_Moderate PP1 PP3

• Not Met criteria codes: PP4 PM2

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

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.

Met criteria codes

• 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)
• PS4: Case Control Study with lower CI ≥1.5 (16958054, 21787400)
• PS3_Moderate: Non-functional in multiple different protein assays (PMIDs:19431188,18634022)
• 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)

Not Met criteria codes

• PP4: Mother (HET) and 3 affected siblings (HOM) show normal size and levels of ATM protein (PMID 9463314)
• 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%.

Approved on: 2022-03-09

Published on: 2022-07-11