ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.133C>T (p.Arg45Trp) (rs3218684)

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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 RCV000129025 SCV000172930 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000199094 SCV000254058 uncertain significance Ataxia-telangiectasia syndrome 2019-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 45 of the ATM protein (p.Arg45Trp). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs3218684, 0.02%). This variant has been observed in individuals affected with breast cancer and renal cancer (PMID: 11897822, 26689913). It has also been found in an unaffected individual (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 140832). 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 disruptive, but these predictions have not been confirmed by published functional studies. 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 RCV000219679 SCV000278808 uncertain significance not provided 2017-06-22 criteria provided, single submitter clinical testing This variant is denoted ATM c.133C>T at the cDNA level, p.Arg45Trp (R45W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been identified in an individual with a history of clear cell renal carcninoma (Lu 2015) as well as in 1/215 breast cancer cases and 0/200 controls in a Finnish study (Allinen 2002) and in 0/4112 breast cancer cases and 1/2399 controls in a later meta-analysis (Tavtigian 2009). ATM Arg45Trp was observed at an allele frequency of 0.02% (2/10224) in individuals of African ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Arg45Trp occurs at a position that is not conserved and is not located in a functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether ATM Arg45Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000129025 SCV000681970 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001199867 SCV001370605 uncertain significance not specified 2020-05-07 criteria provided, single submitter clinical testing Variant summary: ATM c.133C>T (p.Arg45Trp) results in a non-conservative amino acid change located in the Telomere length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251182 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.133C>T has been reported in the literature in individuals affected with breast cancer (example, Allinen_2002, Tung_2015). It has also been reported as a rare germline variant in the TGCA (The Cancer Genome Atlas) cohort (Lu_2015) and in at-least one unaffected control individual (Tavtigian_2009). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia or with breast cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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