ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8000T>C (p.Met2667Thr) (rs1060501566)

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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 RCV000567349 SCV000660653 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000587442 SCV000694367 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing Variant summary: The ATM c.8000T>C (p.Met2667Thr) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 125974 control chromosomes. But has been reported in one breast cancer patient from the literature, without strong evidence for causality, and has not been reported by other databases or clinical labs. Taken together, this variant is classified as VUS.
Invitae RCV000465477 SCV000546743 uncertain significance Ataxia-telangiectasia syndrome 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 2667 of the ATM protein (p.Met2667Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 19781682, 11505391). ClinVar contains an entry for this variant (Variation ID: 407502). 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.

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