ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1271C>A (p.Pro424His) (rs147472613)

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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 RCV000164384 SCV000215019 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-02 criteria provided, single submitter clinical testing Insufficient evidence
GeneDx RCV000218574 SCV000278810 uncertain significance not provided 2018-05-03 criteria provided, single submitter clinical testing This variant is denoted ATM c.1271C>A at the cDNA level, p.Pro424His (P424H) at the protein level, and results in the change of a Proline to a Histidine (CCT>CAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Pro424His was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Pro424His is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Pro424His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000164384 SCV000292200 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-30 criteria provided, single submitter clinical testing
Invitae RCV000526201 SCV000622245 uncertain significance Ataxia-telangiectasia syndrome 2019-11-20 criteria provided, single submitter clinical testing This sequence change replaces proline with histidine at codon 424 of the ATM protein (p.Pro424His). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and histidine. This variant is present in population databases (rs147472613, ExAC 0.01%). This variant has been observed in an individual with breast cancer (PMID: 30086788). ClinVar contains an entry for this variant (Variation ID: 185031). 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 disruptive, 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.
Integrated Genetics/Laboratory Corporation of America RCV001193062 SCV001361642 uncertain significance not specified 2019-09-20 criteria provided, single submitter clinical testing Variant summary: ATM c.1271C>A (p.Pro424His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 248784 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1271C>A has been reported in the literature in individuals affected with Breast Cancer (Penkert_2018, Tung_2015), however without strong evidence of causality. These reports therefore, do 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 submitters (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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