ClinVar Genomic variation as it relates to human health

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 512 of the CHEK2 protein (p.Leu512Val). This variant is present in population databases (rs17882942, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 21244692, 25186627). ClinVar contains an entry for this variant (Variation ID: 141856). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Published functional studies demonstrate no damaging effect: normal growth in response to DNA damage (PMID: 30851065); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with a personal history of breast cancer (PMID: 21244692, 25186627); This variant is associated with the following publications: (PMID: 21244692, 26787654, 27527004, 16671833, 25186627, 31398194, 31106920, 30851065)

Variant summary: CHEK2 c.1534C>G (p.Leu512Val) 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 8.5e-05 in 235842 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Breast Cancer (8.5e-05 vs 0.00031), allowing no conclusion about variant significance. c.1534C>G has been reported in the literature in individuals affected with Breast Cancer as well as in controls (Calvez-Kelm_2011, Young_2015, Weitzel_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 16671833, 21244692, 30851065, 37449874, 31206626, 26787654). ClinVar contains an entry for this variant (Variation ID: 141856). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

In the published literature, this variant has been reported in individuals affected with breast cancer (PMID: 21244692 (2011), 25186627 (2015), 31206626 (2019)), colorectal cancer ((PMID: 28944238 (2017)) as well as in unaffected individuals (PMID: 31206626 (2019)). This variant was characterized as benign based on an in vivo yeast-based functional assay (PMID: 30851065 (2019)). The frequency of this variant in the general population, 0.0006 (21/35204 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

The p.L512V variant (also known as c.1534C>G), located in coding exon 13 of the CHEK2 gene, results from a C to G substitution at nucleotide position 1534. The leucine at codon 512 is replaced by valine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals diagnosed with breast cancer and in controls across studies (Le Calvez-Kelm F et al. Breast Cancer Res., 2011 Jan;13:R6; Young EL et al. J. Med. Genet., 2016 06;53:366-76; Weitzel JN et al. Cancer. 2019 08;125(16):2829-2836). This variant was also reported in a cohort of 1231 colorectal cancer cases (DeRycke MS et al. Mol Genet Genomic Med. 2017 Sep;5(5):553-569). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This alteration was also reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). This amino acid position is poorly conserved in available vertebrate species. In addition, this missense alteration is predicted to be tolerated by in silico analysis, but In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.