ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1440A>C (p.Leu480Phe) (rs370240037)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165898 SCV000216653 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000233396 SCV000282871 uncertain significance Ataxia-telangiectasia syndrome 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 480 of the ATM protein (p.Leu480Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs370240037, ExAC 0.01%). This variant has been reported in individuals affected with ovarian cancer (PMID: 24448499) and prostate cancer (PMID: 19638463). ClinVar contains an entry for this variant (Variation ID: 186322). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
GeneDx RCV000235274 SCV000293430 uncertain significance not provided 2018-11-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.1440A>C at the cDNA level, p.Leu480Phe (L480F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTA>TTC). This variant has been reported in two individuals with breast cancer, one individual with ovarian cancer, and one individual with prostate cancer, but has also been reported in a healthy control subject (Pugh 2009, Kanchi 2014, Decker 2017). ATM Leu480Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Leu480Phe 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 Leu480Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000165898 SCV000681978 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
Counsyl RCV000233396 SCV000789161 uncertain significance Ataxia-telangiectasia syndrome 2017-01-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779758 SCV000916534 uncertain significance not specified 2017-11-09 criteria provided, single submitter clinical testing Variant summary: The ATM c.1440A>C (p.Leu480Phe) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 6/278204 control chromosomes at a frequency of 0.0000216, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). This variant has been reported in multiple cancer patients without strong evidence supporting causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.

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