ClinVar

Description

Variant summary: ATM c.5063T>C (p.Ile1688Thr) results in a non-conservative amino acid change in 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 0.00013 in 298714 control chromosomes (gnomAD and publication data), and was exclusively observed within the East Asian subpopulation at a frequency of 0.00092 in the gnomAD database. This frequency is slightly lower than expected for a pathogenic variant in ATM causing Breast Cancer (0.00092 vs 0.001), however the variant still might represent a benign polymorphism found predominantly in individuals of East Asian origin. Indeed, a large case-control association study, involving unselected breast cancer (BrC) patients and controls of Japanese ancestry, identified the variant in 3/7051 female BrC cases, but also found the variant in 12/11242 healthy female- and 9/12490 healthy male control individuals, based on their findings the authors of this study concluded that the variant is benign (Momozawa 2018). 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, and all laboratories classified the variant as uncertain significance; however all of these classifications were performed before the publication of the Momozawa study. Based on the evidence outlined above, the variant was classified as likely benign.