ClinVar

Description

Variant summary: ATM c.3919G>A (p.Gly1307Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 251256 control chromosomes, predominantly at a frequency of 0.0029 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 3-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 South Asian origin. c.3919G>A has been reported in the literature in individuals affected with cancer including low grade glioma and breast cancer (e.g. Shayeghi_1998, Lu_2015, Mandelker_2017) but was also reported in non-cancer controls (e.g. Pritchard_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. One submitter in LOVD reports co-occurrence of the variant with 2 undefined pathogenic variants and classifies it as benign. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and one ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.