ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.5278A>G (p.Met1760Val) (rs151327241)

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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 RCV000214190 SCV000277694 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-01 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence
Invitae RCV000234490 SCV000282986 uncertain significance Ataxia-telangiectasia syndrome 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1760 of the ATM protein (p.Met1760Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs151327241, ExAC 0.01%). This variant has been reported in an individual affected with colon cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 233341). 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.
GeneDx RCV000586617 SCV000293757 uncertain significance not provided 2018-03-07 criteria provided, single submitter clinical testing This variant is denoted ATM c.5278A>G at the cDNA level, p.Met1760Val (M1760V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been reported in at least one individual with a personal history of colorectal cancer, whose tumor studies demonstrated mismatch repair proficiency via normal immunohistochemistry (IHC) and/or microsatellite stability (Pearlman 2017). ATM Met1760Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). ATM Met1760Val 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 Met1760Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586617 SCV000694301 uncertain significance not provided 2017-03-16 criteria provided, single submitter clinical testing Variant summary: The ATM c.5278A>G (p.Met1760Val) variant located in the Armadillo-type fold domain (via InterPro) involves the alteration of a conserved nucleotide that 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/121300 (1/40485), which does not exceed the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/999 for Breast Cancer. Multiple publications have cited the variant in affected individuals, although with limited information (ie, lack of co-occurrence and/or cosegregation data). Multiple clinical diagnostic laboratories 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)."
Fulgent Genetics,Fulgent Genetics RCV000763706 SCV000894586 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000214190 SCV000903119 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-30 criteria provided, single submitter clinical testing

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