ClinVar

Description

Variant summary: ATM c.7740A>C (p.Arg2580Ser) 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 0.0003 in 152224 control chromosomes, predominantly at a frequency of 0.002 within the Latino subpopulation in the gnomAD database (v3). The observed variant frequency within Latino 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), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.7740A>C has been reported in the literature in individuals affected with breast cancer, ovarian cancer and Chronic Lymphocytic Leukemia patients (Tung_2016, Lu_2015, Tiao_2017, Dutil_2019, Tsaousis_2019, Da Costa_2020). These report(s) 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. The following publications have been ascertained in the context of this evaluation (PMID: 26689913, 26787654, 26976419, 28652578, 31159747, 32039725, 31780696). ClinVar contains an entry for this variant (Variation ID: 127448). Based on the evidence outlined above, the variant was classified as likely benign.