ClinVar

Description

Variant summary: CHEK2 c.319+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. A recent report confirmed this prediction, by demonstrating that the variant didn't produce any full length transcripts in a splicing reporter minigene assay (Sanoguera-Miralles_2023). The variant allele was found at a frequency of 0.0001 in 282,228 control chromosomes (gnomAD v2.1), however in some subpopulations e.g. in the Finnish and Estonian the variant was reported with much higher frequencies, i.e. 0.0006 and 0.0019 respectively. These subpopulation frequencies are higher than the estimated maximum expected for a pathogenic variant in CHEK2 causing Breast Cancer phenotype (0.00031). The variant has been reported in patients with breast cancer and other tumor phenotypes, including e.g. microsatellite-stable colorectal cancer and Cowden-like syndrome (e.g. de Miranda_2013, Susswein_2015, Leedom_2016, Rohlin_2016, Dominguez-Valentin_2017). In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 20/60,466 cases, and 7/53,461 controls (Dorling_2021, reported through LOVD). A case control study in the Finnish population, suggested that this variant is associated with elevated risk of breast cancer (Nurmi_2022). While another case-control study performed in Estonians showed that the relative frequency of the variant in the in the general population is 0.09%, and in variant carriers most breast cancer cases were diagnosed after the age of 50y (Pavlovica_2022). The following publications have been ascertained in the context of this evaluation (PMID: 23960188, 26681312, 27696107, 28608266, 27751358, 33471991, 35314380, 36551643, 37725924). 13 other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic (n=3) or likely pathogenic (n=10). Based on the evidence outlined above, the variant was classified as pathogenic.