ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7316T>C (p.Val2439Ala) (rs776266049)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164769 SCV000215445 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (benign)
GeneDx RCV000590493 SCV000617374 uncertain significance not provided 2018-11-21 criteria provided, single submitter clinical testing This variant is denoted ATM c.7316T>C at the cDNA level, p.Val2439Ala (V2439A) at the protein level, and results in the change of a Valine to an Alanine (GTA>GCA). Case-control studies observed this variant in individuals with a personal and/or family history of breast and/or ovarian cancer, but not in healthy controls (Thorstenson 2003, Tavtigian 2009). Additionally, this variant was reported in a compound heterozygous state with another ATM variant, in a pediatric patient undergoing whole exome sequencing for short stature; however, other variants were also identified (Guo 2014). ATM Val2439Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the FAT 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 Val2439Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000543915 SCV000622734 uncertain significance Ataxia-telangiectasia syndrome 2018-08-16 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 2439 of the ATM protein (p.Val2439Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs776266049, ExAC 0.002%). This variant has been reported in individuals affected with breast cancer (PMID: 12810666, 19781682). ClinVar contains an entry for this variant (Variation ID: 185361). 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.
Color RCV000164769 SCV000682403 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590493 SCV000694349 uncertain significance not provided 2017-06-09 criteria provided, single submitter clinical testing Variant summary: The ATM c.7316T>C (p.Val2439Ala) variant located in the PIK-related kinase domain (via InterPro) involves the alteration of a conserved nucleotide and 2/3 in silico tools (SNPsandGO and Mutation Taster not captured due to low reliability index and p-value, respectively) predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 1/117176 control chromosomes at a frequency of 0.0000085, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). Multiple publications cite the variant in affected individuals, although with limited information (ie, lack of co-occurrence and cosegregation data). In addition, a clinical diagnostic laboratory classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."

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