ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2396C>T (p.Ala799Val) (rs199954262)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254631 SCV000209701 likely benign not specified 2017-12-06 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.
Ambry Genetics RCV000159693 SCV000216440 likely benign Hereditary cancer-predisposing syndrome 2018-08-21 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
Invitae RCV000472551 SCV000547139 uncertain significance Ataxia-telangiectasia syndrome 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 799 of the ATM protein (p.Ala799Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is present in population databases (rs199954262, ExAC 0.009%). This variant has been reported in an individual affected with renal clear cell carcinoma (PMID: 26689913), and in an individual undergoing Lynch syndrome testing (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 181928). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
Integrated Genetics/Laboratory Corporation of America RCV000254631 SCV000694221 uncertain significance not specified 2019-11-25 criteria provided, single submitter clinical testing Variant summary: ATM c.2396C>T (p.Ala799Val) 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 3.8e-05 in 316526 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (3.8e-05 vs 0.001), allowing no conclusion about variant significance. c.2396C>T has been reported in the literature in individuals affected with Lynch syndrome-associated cancer and/or polyps and kidney renal clear cell carcinoma (Yurgelun_2015, Lu_2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported (ATM unspecified variant; MSH2 c.1576del, p.Thr526Profs*17; ATM, exons 61-62 deletion) (Yurgelun_2015, one clinical laboratory), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as likely benign (4x) and uncertain significance (2x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
GeneKor MSA RCV000159693 SCV000821838 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color RCV000159693 SCV000903122 likely benign Hereditary cancer-predisposing syndrome 2015-04-24 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000159693 SCV000787852 likely benign Hereditary cancer-predisposing syndrome 2017-10-30 no assertion criteria provided clinical testing

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