ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2281A>T (p.Thr761Ser) (rs2235011)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129351 SCV000184115 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Insufficient evidence
Color RCV000129351 SCV000911210 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
GeneDx RCV000586568 SCV000209699 uncertain significance not provided 2018-05-31 criteria provided, single submitter clinical testing This variant is denoted ATM c.2281A>T at the cDNA level, p.Thr761Ser (T761S) at the protein level, and results in the change of a Threonine to a Serine (ACT>TCT). This variant has been reported in at least one individual with breast cancer (Bernstein 2010). In a large case-control meta-analysis, this variant was identified in 1/2,399 control subjects but not observed among 4,112 breast cancer patients (Tavtigian 2009). ATM Thr761Ser was observed at an allele frequency of 0.07% (17/24,036) 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 evidence, it is unclear whether ATM Thr761Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586568 SCV000694215 uncertain significance not provided 2016-07-15 criteria provided, single submitter clinical testing Variant summary: The ATM c.2281A>T (p.Thr761Ser) variant causes a missense change involving a non-conserved nucleotide with 5/5 in silico tools 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 7/121262 (1/17322), predominantly in the African cohort, 7/10368 (1/1481), 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 of interest in affected individuals with limited information (ie, lack of phenotypic, co-occurrence and cosegregation data). In addition, multiple reputable databases/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.
Invitae RCV000122833 SCV000166091 uncertain significance Ataxia-telangiectasia syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 761 of the ATM protein (p.Thr761Ser). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs2235011, ExAC 0.07%). This variant has been reported in the literature in an individual affected with breast cancer (PMID: 20305132). ClinVar contains an entry for this variant (Variation ID: 135744). 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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