ClinVar

Description

Variant summary: ATM c.2149C>T (p.Arg717Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 250562 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4e-05 vs 0.004), allowing no conclusion about variant significance. c.2149C>T has been reported in the literature in individuals affected with personal and/or family history of breast and/or ovarian cancer, and other tumor phenotypes (e.g. Fang_2013, Petereit_2013, Girard_2019, Tsaousis_2019, Dorling_2021,), however it was also reported in several healthy controls (e.g. Momozawa_2018, Dorling_2021). These report(s) 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. Nine other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.