ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.131A>G (p.Asp44Gly) (rs150143957)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166071 SCV000216834 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-03 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000197254 SCV000254057 uncertain significance Ataxia-telangiectasia syndrome 2020-01-07 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 44 of the ATM protein (p.Asp44Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs150143957, ExAC 0.06%). This variant has not been reported in the literature in individuals with an ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 186471). 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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 RCV000590355 SCV000278807 uncertain significance not provided 2018-04-11 criteria provided, single submitter clinical testing This variant is denoted ATM c.131A>G at the cDNA level, p.Asp44Gly (D44G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Asp44Gly was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Asp44Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000166071 SCV000681966 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001255212 SCV000694177 uncertain significance not specified 2020-08-07 criteria provided, single submitter clinical testing Variant summary: ATM c.131A>G (p.Asp44Gly) 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 0.00019 in 143258 control chromosomes, predominantly at a frequency of 0.0006 within the African or African-American subpopulation in the gnomAD database (v3 genomes dataset). This frequency is somewhat lower than the maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.0006 vs 0.001), allowing no conclusion about variant significance. In addition, this variant has been reported in 2/2559 African American women and 1/7325 European American women, who were older than age 70 and cancer free (in the FLOSSIES database). The variant, c.131A>G, has also been reported in the literature in African- or African-American individuals affected with Breast Cancer (Haiman_2013, Tung_2015, Adedokun_2020). These reports however do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl RCV000197254 SCV000797741 uncertain significance Ataxia-telangiectasia syndrome 2018-02-08 criteria provided, single submitter clinical testing
Mendelics RCV000197254 SCV001138425 uncertain significance Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing

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