ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1073A>G (p.Asn358Ser) (rs149636614)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115133 SCV000186618 likely benign Hereditary cancer-predisposing syndrome 2018-02-16 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,Sub-population frequency in support of benign classification (not ava blue, manual h-w)
Color RCV000115133 SCV000910676 likely benign Hereditary cancer-predisposing syndrome 2015-09-23 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587788 SCV000861181 uncertain significance not provided 2018-05-25 criteria provided, single submitter clinical testing
GeneDx RCV000587788 SCV000149042 uncertain significance not provided 2018-10-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.1073A>G at the cDNA level, p.Asn358Ser (N358S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). ATM Asn358Ser was reported in an individual with breast cancer, in an individual with a personal history of a Lynch syndrome-related cancer and/or colon polyps, and in an individual undergoing multigene hereditary cancer panel testing (Yurgelun 2015, Mu 2016, Decker 2017). This variant was observed at an allele frequency of 0.23% (55/23,886) in individuals of African ancestry in large population cohorts (Lek 2016). ATM Asn358Ser is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Asn358Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000211956 SCV000593496 uncertain significance not specified 2015-09-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000211956 SCV000694170 likely benign not specified 2018-05-21 criteria provided, single submitter clinical testing Variant summary: ATM c.1073A>G (p.Asn358Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within African control individuals in the gnomAD database is approximately 2.3 fold of 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 African origin. The variant, c.1073A>G, has been reported in the literature in individuals affected with Lynch Syndrome (Yurgelun_2015) and Breast Cancer (Decker_2017), but also in controls (Tiao_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. 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 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Invitae RCV000196425 SCV000254054 uncertain significance Ataxia-telangiectasia syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 358 of the ATM protein (p.Asn358Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs149636614, ExAC 0.2%). This variant has been reported in an individual affected with a Lynch syndrome-associated cancer or colorectal polyps (PMID: 25980754) and an individual with breast cancer (PMID: 28779002). ClinVar contains an entry for this variant (Variation ID: 127329). 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 serine 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 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.

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