Submissions for variant NM_000051.4(ATM):c.1972G>A (p.Asp658Asn)

dbSNP: rs1343017824

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000795417	SCV000934880	uncertain significance	Ataxia-telangiectasia syndrome	2025-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 658 of the ATM protein (p.Asp658Asn). This variant is present in population databases (no rsID available, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 642029). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002422702	SCV002721353	likely benign	Hereditary cancer-predisposing syndrome	2025-01-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Baylor Genetics	RCV003467347	SCV004210238	uncertain significance	Familial cancer of breast	2023-06-26	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000795417	SCV002083993	uncertain significance	Ataxia-telangiectasia syndrome	2020-08-17	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004740453	SCV005355092	uncertain significance	ATM-related disorder	2024-09-20	no assertion criteria provided	clinical testing	The ATM c.1972G>A variant is predicted to result in the amino acid substitution p.Asp658Asn. This variant has been reported in multiple healthy control individuals (Supplementary data 1, Momozawa et al. 2018. PubMed ID: 30287823; Supplementary Table 2, Okawa et al. 2022. PubMed ID: 36243179). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant has an interpretation of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/642029/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.