ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8895G>C (p.Leu2965Phe) (rs200899512)

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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 RCV000115271 SCV000215495 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000115271 SCV000905060 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-12 criteria provided, single submitter clinical testing
GeneDx RCV000212092 SCV000149180 uncertain significance not provided 2018-10-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.8895G>C at the cDNA level, p.Leu2965Phe (L2965F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTG>TTC). This variant has been reported in at least two individuals with breast cancer (Hauke 2018). ATM Leu2965Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in FATC Domain (Stracker 2013). 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 Leu2965Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000463179 SCV000546668 uncertain significance Ataxia-telangiectasia syndrome 2018-09-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 2965 of the ATM protein (p.Leu2965Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature in an individual from a study of the risk of breast cancer, but not clear if this individual is in breast cancer cases or control group (PMID: 21787400). ClinVar contains an entry for this variant (Variation ID: 127465). 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, this variant has uncertain impact on ATM function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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