ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4304A>G (p.Lys1435Arg) (rs769980220)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567537 SCV000672704 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000567537 SCV000687538 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-05 criteria provided, single submitter clinical testing
Invitae RCV000627974 SCV000748861 uncertain significance Ataxia-telangiectasia syndrome 2017-11-17 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 1435 of the ATM protein (p.Lys1435Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs769980220, ExAC 0.002%). This variant has not been reported in the literature in individuals with ATM-related disease. 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 arginine 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.
Integrated Genetics/Laboratory Corporation of America RCV000780898 SCV000918533 uncertain significance not specified 2018-03-30 criteria provided, single submitter clinical testing Variant summary: ATM c.4304A>G (p.Lys1435Arg) results in a 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 4.1e-06 in 245272 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.4304A>G, has been reported in the literature in control individuals from a case-control study (Tiao_2017). This report does not provide any conclusions about an association of the variant with Breast Cancer. 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 "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.

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