ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1960C>A (p.Gln654Lys) (rs528165789)

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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 RCV000165083 SCV000215786 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000165083 SCV000902998 likely benign Hereditary cancer-predisposing syndrome 2017-01-30 criteria provided, single submitter clinical testing
GeneDx RCV000254742 SCV000322091 uncertain significance not provided 2018-08-10 criteria provided, single submitter clinical testing This variant is denoted ATM c.1960C>A at the cDNA level, p.Gln654Lys (Q654K) at the protein level, and results in the change of a Glutamine to a Lysine (CAG>AAG). This variant has been observed in at least three individuals with breast cancer, an individual with colorectal cancer, and in another individual with an unknown cancer type, but has also been reported in healthy controls (Maillet 2002, Tavtigian 2009, Petereit 2013, Tung 2016, Decker 2017, Tiao 2017, Yurgelun 2017). ATM Gln654Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Gln654Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000122828 SCV000166085 uncertain significance Ataxia-telangiectasia syndrome 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 654 of the ATM protein (p.Gln654Lys). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and lysine. This variant is present in population databases (rs528165789, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer (PMID: 12362033, 19781682, 26976419), colorectal cancer (PMID: 28135145) and unspecified cancer (PMID: 24416720). ClinVar contains an entry for this variant (Variation ID: 135739). 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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