ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.4414T>G (p.Leu1472Val) (rs539676759)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115195 SCV000216988 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000115195 SCV000292154 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515407 SCV000611363 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000588453 SCV000149104 uncertain significance not provided 2018-12-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.4414T>G at the cDNA level, p.Leu1472Val (L1472V) at the protein level, and results in the change of a Leucine to a Valine (TTG>GTG). This variant has been observed in individuals with breast cancer, in an individual with prostate cancer, in one individual with a Lynch syndrome-associated cancer and/or polyps, and in an individual with renal cell carcinoma (Bernstein 2010, Yurgelun 2015, Decker 2017, Paulo 2018, Yehia 2018). ATM Leu1472Val was observed at an allele frequency of 0.04% (13/34,362) in individuals of Latino ancestry 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 Leu1472Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588453 SCV000694282 uncertain significance not provided 2016-01-04 criteria provided, single submitter clinical testing Variant summary: c.4414T>G affects a non-conserved nucleotide, resulting in amino acid change from Leu to Val. 2/3 in-silico tools predict this variant to be damaging (SNPs&GO and MutationTaster not captured due to low reliability index). This variant is found in 7/115728 control chromosomes at a frequency of 0.0000605, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0005001). In addition, two clinical laboratories classified this variant as VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000206408 SCV000261255 uncertain significance Ataxia-telangiectasia syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 1472 of the ATM protein (p.Leu1472Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs539676759, ExAC 0.03%). This variant has been reported in an individual affected with breast cancer (PMID: 20305132) and an individual with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 127390). 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). 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.
Mendelics RCV000206408 SCV000838541 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000588453 SCV000805564 uncertain significance not provided 2017-06-27 criteria provided, single submitter clinical testing

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