ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4871A>G (p.His1624Arg) (rs56354559)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122854 SCV000166112 uncertain significance Ataxia-telangiectasia syndrome 2020-01-01 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 1624 of the ATM protein (p.His1624Arg). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and arginine. This variant is present in population databases (rs56354559, ExAC 0.07%). This variant has been observed in an individual affected with uterine corpus endometrial carcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 135757). 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.
Ambry Genetics RCV000129349 SCV000184113 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-25 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient evidence
GeneDx RCV000587947 SCV000209743 uncertain significance not provided 2018-05-31 criteria provided, single submitter clinical testing This variant is denoted ATM c.4871A>G at the cDNA level, p.His1624Arg (H1624R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). ATM His1624Arg was observed in an individual with endometrial cancer (Lu 2015). Additionally, this variant was not observed among 4,112 breast cancer patients, but was identified in 1/2,399 control subjects in a large case-control meta-analysis (Tavtigian 2009). ATM His1624Arg was observed at an allele frequency of 0.06% (16/24,034) in individuals of African 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 information, it is unclear whether ATM His1624Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587947 SCV000694293 uncertain significance not provided 2016-07-15 criteria provided, single submitter clinical testing Variant summary: The ATM c.4871A>G (p.His1624Arg) variant causes a missense change involving a conserved nucleotide with 2/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 11/121382 (1/11035), predominantly in the African cohort, 7/10404 (1/1486), which does not exceed the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/252 for Ataxia-Telangiectasia. Multiple publications cite the variant in affected individuals, although with limited information (ie, lack of co-occurrence and cosegregation information). Multiple reputable clinical laboratories cite the variant as "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Color RCV000129349 SCV000903140 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-20 criteria provided, single submitter clinical testing

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