ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.125A>G (p.His42Arg) (rs201773026)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115139 SCV000184638 likely benign Hereditary cancer-predisposing syndrome 2018-05-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Subpopulation frequency in support of benign classification
Color RCV000115139 SCV000902707 likely benign Hereditary cancer-predisposing syndrome 2016-07-26 criteria provided, single submitter clinical testing
GeneDx RCV000211940 SCV000149048 likely benign not specified 2018-02-19 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.
Integrated Genetics/Laboratory Corporation of America RCV000211940 SCV000694175 likely benign not specified 2018-07-09 criteria provided, single submitter clinical testing Variant summary: ATM c.125A>G (p.His42Arg) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.125A>G has been reported in the literature in individuals but with limited information (Jiang_2016, Lu_2015, Haiman_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer or Ataxia-Telangiectasia. Co-occurrences with other pathogenic variant(s) have been reported (MSH6 c.3936_3951delTATTCAAAAGGGACAT (p.Ile1313fsX9)). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as likely benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000231946 SCV000282868 uncertain significance Ataxia-telangiectasia syndrome 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 42 of the ATM protein (p.His42Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs201773026, ExAC 0.2%). This variant has been observed in an individual affected with stomach adenocarcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 127335). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Mendelics RCV000231946 SCV000838466 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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