ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2887A>G (p.Met963Val) (rs374353016)

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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 RCV000132462 SCV000187556 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-13 criteria provided, single submitter clinical testing The p.M963V variant (also known as c.2887A>G), located in coding exon 18 of the ATM gene, results from an A to G substitution at nucleotide position 2887. The methionine at codon 963 is replaced by valine, an amino acid with highly similar properties. This alteration has been observed in a cohort of 1040 patients with advanced cancer who were tested for germline mutations in 76 cancer predisposition genes (Mandelker D et al. JAMA. 2017 09;318:825-835). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000168295 SCV000218973 uncertain significance Ataxia-telangiectasia syndrome 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 963 of the ATM protein (p.Met963Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs374353016, ExAC 0.04%). This variant has been observed in an individual with breast cancer, as well as an individual with unspecified cancer (PMID: 28873162, 29684080). ClinVar contains an entry for this variant (Variation ID: 142966). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0. The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 RCV000236226 SCV000292902 uncertain significance not provided 2019-10-15 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with an unspecified cancer (Mandelker 2017); This variant is associated with the following publications: (PMID: 28873162)
Color Health, Inc RCV000132462 SCV000903008 likely benign Hereditary cancer-predisposing syndrome 2015-09-22 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000236226 SCV001143103 uncertain significance not provided 2018-12-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001201309 SCV001372448 uncertain significance not specified 2021-02-05 criteria provided, single submitter clinical testing Variant summary: ATM c.2887A>G (p.Met963Val) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 298826 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.2887A>G has been reported in the literature in individuals affected with different types of cancer (Mandelker_2017, Yehia_2018, Bishop_2020, Fujita_2020). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or breast cancer. Co-occurrence with a pathogenic variant has been reported (BRCA2 c.658_659delGT, p.Val220IlefsX4), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000168295 SCV001462129 uncertain significance Ataxia-telangiectasia syndrome 2020-04-17 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355859 SCV001550865 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Met963Val variant was not identified in the literature nor was it identified in the COGR, Cosmic, MutDB, or LOVD 3.0 database. The variant was identified in dbSNP (ID: rs374353016) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and GeneDx). The variant was identified in control databases in 13 of 277192 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 10 of 24032 chromosomes (freq: 0.0004), Latino in 2 of 34416 chromosomes (freq: 0.00006), European in 1 of 126700 chromosomes (freq: 0.000008); it was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Met963 residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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