ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6179G>A (p.Arg2060His) (rs376521407)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122869 SCV000166127 uncertain significance Ataxia-telangiectasia syndrome 2020-10-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 2060 of the ATM protein (p.Arg2060His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 12673797) and an individual with breast cancer and skin cancers (Invitae). However, in these individuals, a pathogenic allele was also identified in ATM (phase unknown), which suggests that this c.6179G>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 135765). 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. 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.
Ambry Genetics RCV000131768 SCV000186814 likely benign Hereditary cancer-predisposing syndrome 2018-02-13 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
GeneDx RCV000212041 SCV000209791 uncertain significance not provided 2018-09-21 criteria provided, single submitter clinical testing This variant is denoted ATM c.6179G>A at the cDNA level, p.Arg2060His (R2060H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant was observed in an individual with breast cancer and in an individual with prostate cancer (Bernstein 2003, Carneiro 2018). ATM Arg2060His was not observed in large population cohorts (Lek 2016). This variant is located in the FAT domain (Stracker 2013). 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 Arg2060His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000131768 SCV000687677 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-15 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 2060 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer, although the individual was found to also have a co-occuring ATM germline mutation (PMID: 12673797). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779793 SCV000916596 uncertain significance not specified 2021-05-29 criteria provided, single submitter clinical testing Variant summary: ATM c.6179G>A (p.Arg2060His) results in a non-conservative amino acid change located in the PIK-related kinase (IPR014009) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251258 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6179G>A, has been reported in the literature in one individual affected with breast cancer in whom another ATM variant reported as 6405insTT was identified (Bernstein_2003). The phase of these variants were not provided in this report. These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia/Breast Cancer. The same co-occurrence with another pathogenic variant has also been observed at our laboratory (ATM c.6404_6405insTT, p.Leu2135_Arg2136insTer), providing supporting evidence for a benign role. 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 (VUS, n=3; likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

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