ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1009C>T (p.Arg337Cys) (rs138398778)

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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 RCV000115130 SCV000186506 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000115130 SCV000681943 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656756 SCV000341173 uncertain significance not provided 2016-05-30 criteria provided, single submitter clinical testing
GeneDx RCV000656756 SCV000149039 uncertain significance not provided 2018-09-04 criteria provided, single submitter clinical testing This variant is denoted ATM c.1009C>T at the cDNA level, p.Arg337Cys (R337C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has been observed in individuals with breast cancer, thyroid cancer, chronic lymphocytic leukemia, or prostate cancer, but has also been observed in controls (Broeks 2008, Zick 2015, Decker 2017, Tiao 2017, Isaacsson Velho 2018). ATM Arg337Cys was observed at an allele frequency of 0.018% (6/34,376) in individuals of Latino ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Arg337Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780894 SCV000918528 uncertain significance not specified 2018-07-13 criteria provided, single submitter clinical testing Variant summary: ATM c.1009C>T (p.Arg337Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.2e-05 in 281750 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (8.2e-05 vs 0.001), allowing no conclusion about variant significance. c.1009C>T has been reported in the literature in individuals affected with Breast Cancer without strong evidence for pathogenicity. Thus, 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 - variant not specified (ClinVar); MSH2 c.2021G>A, p.Gly674Asp (internal LCA specimen)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000168399 SCV000219092 uncertain significance Ataxia-telangiectasia syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 337 of the ATM protein (p.Arg337Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs138398778, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer and prostate cancer (PMID: 19781682, 17393301, 29368341). This variant has also been observed in an individual with prostate cancer (Invitae). However, in that individual, a likely pathogenic allele was also identified in ATM, which suggests that this c.1009C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 127327). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this sequence change is likely to be disruptive, but 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.
PreventionGenetics RCV000656756 SCV000805487 uncertain significance not provided 2017-10-16 criteria provided, single submitter clinical testing

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