ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.488A>G (p.Gln163Arg)

gnomAD frequency: 0.00001  dbSNP: rs876660598
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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 RCV000222208 SCV000278157 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-01 criteria provided, single submitter clinical testing The p.Q163R variant (also known as c.488A>G), located in coding exon 4 of the ATM gene, results from an A to G substitution at nucleotide position 488. The glutamine at codon 163 is replaced by arginine, an amino acid with highly similar properties. This alteration was detected along with another missense alteration in ATM in a patient with some features of ataxia telangiectasia (A-T), including ataxia and elevated AFP, but no telangiectasia by the age of 7 years old. In addition, cell lines derived from this patient showed normal response to ionizing radiation (Jacquemin V et al. Eur J Hum Genet, 2012 Mar;20:305-12). This alteration was also detected in a study of 1054 BRCA-negative Hispanic women with hereditary breast cancer and 1199 controls (Weitzel JN et al. Cancer, 2019 08;125:2829-2836). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000818786 SCV000959418 uncertain significance Ataxia-telangiectasia syndrome 2023-01-28 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change does not substantially affect ATM function (PMID: 22071889). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 233723). This missense change has been observed in individual(s) with clinical features of ataxia telangiectasia (PMID: 22071889). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 163 of the ATM protein (p.Gln163Arg).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003226257 SCV003922728 uncertain significance not specified 2023-03-27 criteria provided, single submitter clinical testing Variant summary: ATM c.488A>G (p.Gln163Arg) results in a conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) 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 251328 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.488A>G has been reported in the literature in one individual with non-defined diagnosis, but presenting some features of A-T (ataxia and increased level of AFP) (Jacquemin_2012) and one individual affected with breast cancer (Weitzel_2019). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics RCV004567652 SCV005055920 uncertain significance Familial cancer of breast 2024-03-22 criteria provided, single submitter clinical testing
Natera, Inc. RCV000818786 SCV002093941 uncertain significance Ataxia-telangiectasia syndrome 2020-12-28 no assertion criteria provided clinical testing

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