Submissions for variant NM_000051.4(ATM):c.2074C>T (p.Arg692Cys)

gnomAD frequency: 0.00001  dbSNP: rs765965513

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164063	SCV000214673	likely benign	Hereditary cancer-predisposing syndrome	2018-08-28	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	RCV000168071	SCV000218725	uncertain significance	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 692 of the ATM protein (p.Arg692Cys). This variant is present in population databases (rs765965513, gnomAD 0.002%). This missense change has been observed in individual(s) with clinical features of ATM-related conditions (PMID: 26898890, 28652578, 34326862). ClinVar contains an entry for this variant (Variation ID: 184752). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
GeneDx	RCV000219263	SCV000278813	uncertain significance	not provided	2024-01-16	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer and in unaffected controls (PMID: 26898890, 28779002, 33471991); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26898890, 27499925, 28779002, 28652578, 33471991)
Color Diagnostics, LLC DBA Color Health	RCV000164063	SCV000911566	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 692 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 reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 26898890, 28779002). In a large international case-control study, this variant was absent in 60466 breast cancer cases and reported in 1/53460 controls (PMID: 33471991). This variant has been identified in 3/251328 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	RCV000780902	SCV000918538	uncertain significance	not specified	2018-04-06	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2074C>T (p.Arg692Cys) 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 8.1e-06 in 246110 control chromosomes. This frequency is lower than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (8.1e-06 vs 0.004), allowing no conclusion about variant significance. c.2074C>T has been reported in the literature in an individual affected with breast cancer (Caminsky 2016). This report does not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting classifications, 2 calling it a VUS and 1 calling it a Likely Benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000164063	SCV002534044	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-11	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150012	SCV003837830	uncertain significance	Breast and/or ovarian cancer	2023-03-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003316015	SCV004020032	likely benign	Familial cancer of breast	2023-03-07	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].
Baylor Genetics	RCV003316015	SCV004207115	uncertain significance	Familial cancer of breast	2024-01-23	criteria provided, single submitter	clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV003483533	SCV004228281	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-08	criteria provided, single submitter	curation	ATM specific: AGVGD Class0, SIFT: Tolerated, outside of FATKIN-domain, Found in trans with ATM frameshift variant in a 70 year old patient without signs of AT. According to the ACMG standard criteria we chose these criteria: BP4 (supporting benign): BP4 (ClinGen Interpretation Guidelines for ATM Version 1.1: REVEL score <.249), BS2 (strong benign): Found in trans with ATM frameshift variant in a 70 year old patient without signs of AT
PreventionGenetics, part of Exact Sciences	RCV004739514	SCV005360067	uncertain significance	ATM-related disorder	2024-05-02	no assertion criteria provided	clinical testing	The ATM c.2074C>T variant is predicted to result in the amino acid substitution p.Arg692Cys. This variant has been reported in individuals with a history of breast and/or ovarian cancer, as well as a colorectal tumor specimen (Caminsky et al. 2016. PubMed ID: 26898890, Table S15; Decker et al. 2017. PubMed ID: 28779002, Table S5; Crobach et al. 2016. PubMed ID: 27499925, Table S3). It has also been reported in a control individual from a chronic lymphocytic leukemia cohort (Tiao et al. 2017. PubMed ID: 28652578, Table S6). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/184752/). 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.