ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3190A>G (p.Met1064Val) (rs79431304)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214272 SCV000273017 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-06 criteria provided, single submitter clinical testing The p.M1064V variant (also known as c.3190A>G), located in coding exon 21 of the ATM gene, results from an A to G substitution at nucleotide position 3190. The methionine at codon 1064 is replaced by valine, an amino acid with highly similar properties. This alteration has been reported with a carrier frequency of 0.00014 in 7,051 unselected breast cancer patients and was not observed in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun 2018 10;9(1):4083). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl RCV000671975 SCV000797024 uncertain significance Ataxia-telangiectasia syndrome 2018-01-10 criteria provided, single submitter clinical testing
Invitae RCV000671975 SCV000820927 uncertain significance Ataxia-telangiectasia syndrome 2020-10-12 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1064 of the ATM protein (p.Met1064Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs79431304, ExAC 0.03%). This variant has been reported in an individual affected with breast cancer (PMID: 28135048). ClinVar contains an entry for this variant (Variation ID: 229707). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.
Color Health, Inc RCV000214272 SCV000911185 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
GeneDx RCV001546529 SCV001766061 uncertain significance not provided 2019-07-22 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28580595, 28135048, 30287823)
Natera, Inc. RCV000671975 SCV001452066 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing

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