Submissions for variant NM_000051.4(ATM):c.95G>A (p.Arg32His)

gnomAD frequency: 0.00002  dbSNP: rs368161489

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001721017	SCV000209724	uncertain significance	not provided	2021-08-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV000459267	SCV000546768	uncertain significance	Ataxia-telangiectasia syndrome	2024-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 32 of the ATM protein (p.Arg32His). This variant is present in population databases (rs368161489, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and/or prostate cancer (PMID: 30306255, 31214711). ClinVar contains an entry for this variant (Variation ID: 181945). 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	RCV000562263	SCV000660486	likely benign	Hereditary cancer-predisposing syndrome	2020-01-13	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.
Color Diagnostics, LLC DBA Color Health	RCV000562263	SCV000904429	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 32 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with a personal and/or family history of breast cancer (PMID: 30306255) and an individual affected with prostate cancer (PMID: 31214711). In an international breast cancer case-control meta-analysis, this variant was detected in 1/60466 cases and absent in 53461 unaffected controls (PMID: 33471991). This variant has been identified in 4/251182 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV000562263	SCV002531183	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-15	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV002288671	SCV002579573	uncertain significance	Familial cancer of breast	2022-01-26	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001721017	SCV002771642	uncertain significance	not provided	2022-09-06	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV002288671	SCV004210244	uncertain significance	Familial cancer of breast	2024-01-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001721017	SCV004222314	uncertain significance	not provided	2024-10-28	criteria provided, single submitter	clinical testing	The ATM c.95G>A (p.Arg32His) variant has been reported in the published literature in individuals affected with a personal and/or family history of breast cancer (PMID: 30306255 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)), prostate cancer (PMID: 31214711 (2020)), as well as an individual affected with both colorectal cancer and a sarcoma (PMID: 34326862 (2021)). This variant has also been observed in a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). The frequency of this variant in the general population, 0.000016 (4/251182 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005237593	SCV005886261	uncertain significance	not specified	2025-02-06	criteria provided, single submitter	clinical testing	Variant summary: ATM c.95G>A (p.Arg32His) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251182 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.95G>A has been reported in the literature in individuals affected with congenital heart disease or colorectal sarcoma (Edwards_2020, Bhai_2021). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 32368696). ClinVar contains an entry for this variant (Variation ID: 181945). Based on the evidence outlined above, the variant was classified as uncertain significance.