ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2804C>G (p.Thr935Arg) (rs3218708)

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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 RCV000164443 SCV000215083 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000164443 SCV000903257 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Counsyl RCV000557491 SCV000800472 uncertain significance Ataxia-telangiectasia syndrome 2018-06-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779788 SCV000916590 uncertain significance not specified 2018-08-17 criteria provided, single submitter clinical testing Variant summary: ATM c.2804C>G (p.Thr935Arg) 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 allele was found at a frequency of 1.6e-05 in 246178 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2804C>G has been reported in the literature in an individual affected with Breast Cancer (Mangone_2015). This report does not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 RCV000557491 SCV000622362 uncertain significance Ataxia-telangiectasia syndrome 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 935 of the ATM protein (p.Thr935Arg). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is present in population databases (rs3218708, ExAC 0.05%). This variant has been reported in an individual affected with breast cancer (PMID: 25625042). ClinVar contains an entry for this variant (Variation ID: 185083). 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.

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