Submissions for variant NM_000051.4(ATM):c.7778A>G (p.Gln2593Arg)

gnomAD frequency: 0.00008  dbSNP: rs587779867

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588147	SCV000149164	uncertain significance	not provided	2023-11-09	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25503501, 28503720, 28779002, 30883245, 36845387)
Ambry Genetics	RCV000115255	SCV000185534	likely benign	Hereditary cancer-predisposing syndrome	2020-09-11	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	RCV000197623	SCV000254149	likely benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115255	SCV000537522	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-03	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 2593 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 25503501, 28503720, 28779002, 30883245, 33471991, 34299313). This variant has also been identified in 21/250896 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002228249	SCV000694359	uncertain significance	not specified	2023-03-27	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7778A>G (p.Gln2593Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250896 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (8.4e-05 vs 0.001), allowing no conclusion about variant significance. c.7778A>G has been reported in the literature with classifications ranging from likely benign (example, Maxwell_2014) to VUS (example, Guglielmi_2021) in settings of multigene panel testing of individuals affected with BRCA1/2 negative breast and/or ovarian cancer. It has also been reported in the FLOSSIES database among cancer free women who are older than age 70. These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia Telangiectasia/Breast Cancer/ATM-related disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Counsyl	RCV000197623	SCV000799961	uncertain significance	Ataxia-telangiectasia syndrome	2018-05-14	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV001257470	SCV001434276	uncertain significance	Familial cancer of breast	2019-10-04	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in several individuals with breast cancer (Maxwell 2015, Rummel 2017, Decker 2017). This variant has an overall allele frequency of 0.00008 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. PP3
Sema4, Sema4	RCV000115255	SCV002538160	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-03	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV001257470	SCV002581743	uncertain significance	Familial cancer of breast	2022-08-24	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588147	SCV002774766	likely benign	not provided	2022-12-06	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115255	SCV004228029	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-21	criteria provided, single submitter	clinical testing
Mendelics	RCV004700417	SCV005205586	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
Natera, Inc.	RCV000197623	SCV001462593	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing