ClinVar

Description

Variant summary: CHEK2 c.1513T>A (p.Ser505Thr) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00023 in 281104 control chromosomes, predominantly at a frequency of 0.00083 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. While CHEK2 does have highly homologous pseudogenes, the surrounding region of the variant appears to be unaffected by pseudogene interference via BLAT search. c.1513T>A has been reported in the literature in case control cohorts of Japanese individuals affected with breast cancer and in ethnicity matched unaffected controls (example, Momozawa_2018, Fujita_2020) as well as in settings of multigene panel testing for breast cancer (example, Tung_2015). One of these publications has recently reported a final clinical significance for this variant as "benign" using the ACMG/AMP guidelines (Fujita_2020). Therefore, these report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a yeast based experimental system evaluating the ability to resume cell growth and proliferation by repair of methyl-methanesulfonate (MMS) induced DNA damage (Delimitsou_2019). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.