ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4631A>G (p.Tyr1544Cys) (rs779718362)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236361 SCV000292922 uncertain significance not provided 2018-03-13 criteria provided, single submitter clinical testing This variant is denoted ATM c.4631A>G at the cDNA level, p.Tyr1544Cys (Y1544C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAC>TGC). This variant has been observed in individuals with breast or lung cancer, but has also been observed in a healthy control subject (Lu 2015, Decker 2017). ATM Tyr1544Cys 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 a deleterious effect. Based on currently available evidence, it is unclear whether ATM Tyr1544Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000471874 SCV000546904 uncertain significance Ataxia-telangiectasia syndrome 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1544 of the ATM protein (p.Tyr1544Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs779718362, ExAC 0.006%). This variant has been observed in individuals affected with breast or lung cancer (PMID: 26689913, 25186627). ClinVar contains an entry for this variant (Variation ID: 245791). 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.
Ambry Genetics RCV000566756 SCV000660447 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000566756 SCV000682216 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780886 SCV000918515 uncertain significance not specified 2017-10-20 criteria provided, single submitter clinical testing Variant summary: The ATM c.4631A>G (p.Tyr1544Cys) variant causes a missense change involving the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 8/236132 control chromosomes at a frequency of 0.0000339, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). This variant was found in two breast cancer patients, without strong evidence for pathogenicity (Edvardsen_2007, Tung_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS, until more definitive functional and clinical data become available.

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