ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2836A>G (p.Met946Val) (rs587781992)

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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 RCV000130397 SCV000185256 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-18 criteria provided, single submitter clinical testing The p.M946V variant (also known as c.2836A>G), located in coding exon 17 of the ATM gene, results from an A to G substitution at nucleotide position 2836. The methionine at codon 946 is replaced by valine, an amino acid with highly similar properties. This amino acid position is 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 RCV000168097 SCV000218753 uncertain significance Ataxia-telangiectasia syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 946 of the ATM protein (p.Met946Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs587781992, ExAC 0.01%). This variant has not been reported in the literature in individuals with ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 141763). 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 RCV000485729 SCV000568002 uncertain significance not provided 2020-08-25 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Hauke 2018); This variant is associated with the following publications: (PMID: 29522266)
Fulgent Genetics,Fulgent Genetics RCV000515251 SCV000611353 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130397 SCV000902852 likely benign Hereditary cancer-predisposing syndrome 2016-05-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779792 SCV000916594 uncertain significance not specified 2021-08-29 criteria provided, single submitter clinical testing Variant summary: ATM c.2836A>G (p.Met946Val) results in a conservative amino acid change located in the PIK-related kinase - FAT domain (IPR003151) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251282 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2836A>G in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=5; LB, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Natera, Inc. RCV000168097 SCV001452054 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356743 SCV001551996 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The ATM p.Met946Val variant was identified in 1 of 11178 proband chromosomes (frequency: 0.00009) from German individuals or families with BRCA1/2 negative breast or ovarian cancer (Hauke 2018). The variant was also identified in dbSNP (ID: rs587781992) “With Uncertain significance allele” and ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, GeneDx and Fulgent Genetics (Fulgent Genetics)) and not identified in LOVD 3.0 database. The variant was identified in control databases in 4 of 277036 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: African in 1 of 24038 chromosomes (freq: 0.00004) and European Non-Finnish in 3 of 126682 chromosomes (freq: 0.00002), while not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Met946 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 p.Met946Val variant occurs in the last three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. However, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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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