ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7382G>A (p.Arg2461His) (rs768461085)

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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 RCV000217134 SCV000274850 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Athena Diagnostics Inc RCV000710682 SCV000840960 uncertain significance not provided 2017-09-20 criteria provided, single submitter clinical testing
Color RCV000217134 SCV000682412 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779801 SCV000916605 uncertain significance not specified 2018-11-05 criteria provided, single submitter clinical testing Variant summary: ATM c.7382G>A (p.Arg2461His) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-05 in 268512 control chromosomes (gnomAD and publication). This frequency is not higher than expected for a pathogenic variant in ATM causing Breast Cancer (4.1e-05 vs 0.001), allowing no conclusion about variant significance. c.7382G>A has been reported in the literature in individuals affected with Breast Cancer (Momozawa_2018). However, 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. Four 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.
Invitae RCV000199157 SCV000254144 uncertain significance Ataxia-telangiectasia syndrome 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2461 of the ATM protein (p.Arg2461His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs768461085, ExAC 0.02%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 216230). 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.

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