Submissions for variant NM_000051.4(ATM):c.7740A>C (p.Arg2580Ser)

gnomAD frequency: 0.00031  dbSNP: rs199915459

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589821	SCV000149163	uncertain significance	not provided	2019-01-08	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.7740A>C at the cDNA level, p.Arg2580Ser (R2580S) at the protein level, and results in the change of an Arginine to a Serine (AGA>AGC). This variant has been observed in individuals with breast or ovarian cancer (Lu 2015, Tung 2016). ATM Arg2580Ser was observed at an allele frequency of 0.03% (11/34,414) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Arg2580Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000115254	SCV000186651	likely benign	Hereditary cancer-predisposing syndrome	2018-08-16	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205594	SCV000261019	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855570	SCV000694357	likely benign	not specified	2024-04-25	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7740A>C (p.Arg2580Ser) results in a non-conservative amino acid change in 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 0.0003 in 152224 control chromosomes, predominantly at a frequency of 0.002 within the Latino subpopulation in the gnomAD database (v3). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.7740A>C has been reported in the literature in individuals affected with breast cancer, ovarian cancer and Chronic Lymphocytic Leukemia patients (Tung_2016, Lu_2015, Tiao_2017, Dutil_2019, Tsaousis_2019, Da Costa_2020). These report(s) 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: 26689913, 26787654, 26976419, 28652578, 31159747, 32039725, 31780696). ClinVar contains an entry for this variant (Variation ID: 127448). Based on the evidence outlined above, the variant was classified as likely benign.
GeneKor MSA	RCV000115254	SCV000821873	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000205594	SCV000838596	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000589821	SCV000840963	uncertain significance	not provided	2023-07-07	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is not damaging.
Color Diagnostics, LLC DBA Color Health	RCV000115254	SCV000902816	likely benign	Hereditary cancer-predisposing syndrome	2016-10-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589821	SCV001469959	uncertain significance	not provided	2023-07-07	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 35264596 (2022), 32936981 (2021), 32658311 (2021), 32039725 (2020), 31159747 (2019), 31780696 (2019), 26976419 (2016)), ovarian cancer (PMID: 26689913 (2015)), or prostate cancer (PMID: 31214711 (2020)). In addition, this variant has been reported in control individuals (PMID: 32658311 (2021), 28652578 (2017)). The frequency of this variant in the general population, 0.00023 (8/35436 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.
Sema4, Sema4	RCV000115254	SCV002538137	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-16	criteria provided, single submitter	curation
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153367	SCV003843438	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589577	SCV005084587	likely benign	Familial cancer of breast	2024-06-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Mayo Clinic Laboratories, Mayo Clinic	RCV000589821	SCV005412478	uncertain significance	not provided	2024-01-04	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115254	SCV002050285	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-23	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549572	SCV004728164	likely benign	ATM-related disorder	2024-03-06	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).