Submissions for variant NM_000051.4(ATM):c.3613C>T (p.Arg1205Cys)

gnomAD frequency: 0.00001  dbSNP: rs760928285

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195728	SCV000254088	uncertain significance	Ataxia-telangiectasia syndrome	2025-01-08	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 1205 of the ATM protein (p.Arg1205Cys). This variant is present in population databases (rs760928285, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 216202). 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.
GeneDx	RCV000479830	SCV000572291	uncertain significance	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Momozawa et al., 2018); This variant is associated with the following publications: (PMID: 28652578, 19781682, 30287823)
Ambry Genetics	RCV000562379	SCV000665272	likely benign	Hereditary cancer-predisposing syndrome	2018-06-07	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	RCV000562379	SCV000911420	likely benign	Hereditary cancer-predisposing syndrome	2016-06-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000195728	SCV001138495	uncertain significance	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000195728	SCV001260527	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-13	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192418	SCV001360529	uncertain significance	not specified	2019-10-10	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3613C>T (p.Arg1205Cys) 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 2e-05 in 298592 control chromosomes (gnomAD and Momozawa_2018). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3613C>T has been reported in the literature in an individual affected with Breast Cancer (Momozawa_2018). This report however does not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.631+2T>G; internal LCA sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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 (2 classifying it as VUS, while 2 calling it likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV004786534	SCV005402218	uncertain significance	Familial cancer of breast	2024-01-21	criteria provided, single submitter	clinical testing	The ATM c.3613C>T (p.Arg1205Cys) missense change has a maximum subpopulation frequency of 0.0054% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in an individual with breast cancer (PMID: 30287823). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001192418	SCV005872613	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing