ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.283C>A (p.Gln95Lys) (rs587781545)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159724 SCV000209736 uncertain significance not provided 2018-04-19 criteria provided, single submitter clinical testing This variant is denoted ATM c.283C>A at the cDNA level, p.Gln95Lys (Q95K) at the protein level, and results in the change of a Glutamine to a Lysine (CAG>AAG). This variant has been reported in a pediatric patient with an ependymoma and in an individual with breast cancer (Tung 2015, Zhang 2015). ATM Gln95Lys was observed at an allele frequency of 0.18% (34/18,838) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the region of interaction with p53 & BRCA1 (Tavtigian 2009, 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 Gln95Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000229615 SCV000282913 uncertain significance Ataxia-telangiectasia syndrome 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 95 of the ATM protein (p.Gln95Lys). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and lysine. This variant is present in population databases (rs587781545, ExAC 0.2%). This variant has been observed in individuals affected with breast cancer (PMID: 28580595). ClinVar contains an entry for this variant (Variation ID: 181957). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV000445811 SCV000537548 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000445811 SCV000660459 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-01 criteria provided, single submitter clinical testing Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000764933 SCV000896105 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175058 SCV001338605 uncertain significance not specified 2020-04-23 criteria provided, single submitter clinical testing Variant summary: ATM c.283C>A (p.Gln95Lys) 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 allele was found at a frequency of 0.00012 in 250948 control chromosomes, predominantly at a frequency of 0.0017 within the East Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), suggesting that the variant may be a benign polymorphism found primarily in populations of East Asian origin. c.283C>A has been reported in the literature in individuals of Asian ancestry affected with Breast Cancer (e.g. Chan_2018, Tung_2015, Wang_2019, Xie_2018). These reports 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. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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