ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2021A>G (p.His674Arg) (rs201762714)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129577 SCV000184359 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000129577 SCV000902744 likely benign Hereditary cancer-predisposing syndrome 2016-03-07 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515195 SCV000611347 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000236547 SCV000292868 uncertain significance not provided 2018-05-24 criteria provided, single submitter clinical testing This variant is denoted ATM c.2021A>G at the cDNA level, p.His674Arg (H674R) at the protein level, and results in the change of a Histidine to an Arginine (CAC>CGC). This variant was observed in unaffected control subjects but was absent among cases in two breast cancer case-control studies (Tavtigian 2009, Decker 2017). It has also been reported in one individual with low grade glioma and in at least one individual with an unspecified type of advanced cancer (Lu 2015, Mandelker 2017). ATM His674Arg was observed at an allele frequency of 0.085% (26/30,782) in individuals of South Asian 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM His674Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000129577 SCV000821833 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780908 SCV000918548 uncertain significance not specified 2018-05-25 criteria provided, single submitter clinical testing Variant summary: ATM c.2021A>G (p.His674Arg) 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 was observed with an allele frequency of 0.00016 in 277138 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00016 vs 0.001), allowing no conclusion about variant significance. The variant, c.2021A>G, has not been reported in the literature in individuals affected with Breast Cancer. Co-occurrences with other pathogenic variant(s) have been reported (CHEK2 c.1368dupA, p.Glu457fsX33), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertian significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000168255 SCV000218926 uncertain significance Ataxia-telangiectasia syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 674 of the ATM protein (p.His674Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs201762714, ExAC 0.07%). This variant has been reported in an individual with low grade glioma (PMID: 26689913). In a large meta-analysis studying the association of ATM missense variants with increased risk of breast cancer, this c.2021A>G substitution showed no evidence for increased cancer risk (0/2,531 cases vs. 1/2,245 controls) (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 141183). 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. 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.
Mayo Clinic Health System - Franciscan Health care,Mayo Clinic Health System RCV000181010 SCV000233284 uncertain significance Bilateral Breast Carcinoma 2014-09-25 no assertion criteria provided clinical testing
Mendelics RCV000168255 SCV000838496 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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