ClinVar

Description

Variant summary: CHEK2 c.1169A>G (p.Tyr390Cys) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251046 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1169A>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and in multiple case control studies was reported at a higher frequency in cases than controls (Wang_2015, Aksoy_2022, Adedokun_2020), however these reports do not show strong evidence for causality (segregation data,etc). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least three publications have reported experimental evidence evaluating an impact on protein function, finding that cells expressing the variant of interest display reduced sensitivity to DNA-damaging agents as well as impaired p53 activitation, cell cycle arrest, and apoptosis upon DNA damage as well as reduced kinase activity toward Kap1; cells expressing the CHEK2 Y390C variant behaved similarly to CHEK2-null cells expressing an empty-vector control (e.g., Wang_2015, Luo_2018, Boonen_2022). Additionally, a different variant affecting the same codon has been reported as pathogenic by our lab (p.Tyr390Ser). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.