Submissions for variant NM_000051.4(ATM):c.2494C>T (p.Arg832Cys)

gnomAD frequency: 0.00032  dbSNP: rs2229022

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129082	SCV000183785	likely benign	Hereditary cancer-predisposing syndrome	2018-05-18	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.
GeneDx	RCV000211982	SCV000209704	likely benign	not specified	2017-10-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199664	SCV000254070	likely benign	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000211982	SCV000593499	uncertain significance	not specified	2016-09-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211982	SCV000694227	likely benign	not specified	2024-09-23	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2494C>T (p.Arg832Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 278644 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Breast Cancer (0.00023 vs 0.001), allowing no conclusion about variant significance. c.2494C>T has been reported in the literature with varying phenotypes including Lynch syndrome, breast cancer, chronic lymphocytic leukemia, prostate cancer and pancreatic cancer (e.g. Grant_2015, Nadeu_2016, Schwartz_2019, Skowronska_2012, Paulo_2018, Tung_2016, Yurgelun_2015) but also in controls (e.g. Momozawa_2018, Tavtigian_2009). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. A co-occurrence with a pathogenic variant has been reported following internal testing (SMAD4 c.787+2T>C). A ClinVar submitter reports co-occurrence with another mutation in the ATM gene (phase unknown) for the phenotype of Hereditary cancer-predisposing syndrome (SCV000183785.6). Furthermore, the variant was reported in the FLOSSIES database in 5 women older than age 70 years who have never had cancer. Altogether, these data provide supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 140867). Based on the evidence outlined above, the variant was classified as likely benign.
GeneKor MSA	RCV000129082	SCV000821791	likely benign	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV004700436	SCV000838507	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.
Color Diagnostics, LLC DBA Color Health	RCV000129082	SCV000902655	likely benign	Hereditary cancer-predisposing syndrome	2015-04-24	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000199664	SCV001262551	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587618	SCV002010839	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129082	SCV002532222	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-22	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000587618	SCV004226232	uncertain significance	not provided	2023-06-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492583	SCV004240458	uncertain significance	Breast and/or ovarian cancer	2023-05-05	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211982	SCV004243420	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589620	SCV005083903	likely benign	Familial cancer of breast	2024-05-09	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].
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004589620	SCV005402196	uncertain significance	Familial cancer of breast	2023-11-29	criteria provided, single submitter	clinical testing	The ATM c.2494C>T (p.Arg832Cys) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer and pancreatic cancer (PMID: 26976419, 31432501). To our knowledge, this variant has not been reported in individuals with ataxia telangiectasia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
True Health Diagnostics	RCV000129082	SCV000805213	likely benign	Hereditary cancer-predisposing syndrome	2018-05-08	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551237	SCV000805517	uncertain significance	ATM-related disorder	2024-04-26	no assertion criteria provided	clinical testing	The ATM c.2494C>T variant is predicted to result in the amino acid substitution p.Arg832Cys. This variant has been reported in individuals with early-onset breast cancer (Table S1, Young et al. 2016. PubMed ID: 26787654; Table A2, Tung et al. 2016. PubMed ID: 26976419), suspected Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754), chronic lymphocytic leukemia (Table S8, Nadeu et al. 2016. PubMed ID: 26837699), and pancreatic cancer (Table S1, Grant et al. 2015. PubMed ID: 25479140; Schwartz et al. 2019. PubMed ID: 31432501). This variant is reported in 0.044% of alleles in individuals of African descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/140867/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Natera, Inc.	RCV000199664	SCV001461091	uncertain significance	Ataxia-telangiectasia syndrome	2020-04-16	no assertion criteria provided	clinical testing