ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6784G>C (p.Ala2262Pro) (rs587781674)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129833 SCV000184649 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000460379 SCV000546848 uncertain significance Ataxia-telangiectasia syndrome 2018-05-14 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 2262 of the ATM protein (p.Ala2262Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ataxia-telangiectasia (PMID: 17298726). ClinVar contains an entry for this variant (Variation ID: 141347). 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. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV000779763 SCV000916545 uncertain significance not specified 2018-02-23 criteria provided, single submitter clinical testing Variant summary: ATM c.6784G>C (p.Ala2262Pro) results in a non-conservative amino acid change located in the PIK-related kinase FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 120052 control chromosomes (ExAC). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6784G>C has been reported in the literature in one family in one child affected with Ataxia-Telangiectasia, together with the variant ATM 5419A>G, K1807E (not classified by our lab), and his mother was also a carrier of these two variants (Verlinsky 2007). Since the penetrance of Ataxia-Telangiectasia (0.5) due to this variant appears to be lower than expected (0.8), no conclusions can be drawn from these data. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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