ClinVar Genomic variation as it relates to human health

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in individuals with breast or colorectal cancer, but also in cancer-free controls (Kleibl et al., 2009; Tung et al., 2015; Hauke et al., 2018; Dorling et al., 2021; Momozawa et al., 2018); Published functional studies demonstrate colony growth following DNA damage similar to wild-type a yeast-based assay (Delimitsou et al., 2019); This variant is associated with the following publications: (PMID: 18996005, 25186627, 29522266, 22419737, 19782031, 32906215, 33471991, 32322110, 30287823, 30851065)

This missense variant replaces arginine with glutamine at codon 145 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A yeast functional assay suggests that this variant protein may not impact cell growth and proliferation in the presence of a DNA damaging agent (PMID: 30851065). This variant has been observed in two individuals affected with breast cancer (PMID: 25186627, 30287823) and an individual affected with colorectal cancer (PMID: 18996005). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 4/60466 cases and 7/53461 unaffected controls (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_000143). A different missense variant affecting the same position, p.Arg145Trp, is considered to be disease-causing (ClinVar variation ID: 5592), suggesting that arginine at this position is important for protein structure and function. This variant has been identified in 4/251292 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 145 of the CHEK2 protein (p.Arg145Gln). This variant is present in population databases (rs587781667, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer and colorectal cancer (PMID: 18996005, 25186627). ClinVar contains an entry for this variant (Variation ID: 141337). 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 disruptive. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065). This variant disrupts the forkhead associated domain of the CHEK2 protein, which is essential for protein function (PMID: 30264118, 31843900, 29785007). While functional studies have not been performed to directly test the effect of this variant on CHEK2 protein function, this suggests that disruption of this region of the protein is causative of disease. This variant disrupts the p.Arg145 amino acid residue in CHEK2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11719428, 16982735, 22419737). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.

The p.R145Q variant (also known as c.434G>A), located in coding exon 2 of the CHEK2 gene, results from a G to A substitution at nucleotide position 434. The arginine at codon 145 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been previously reported in an individual of Czech origin with colorectal cancer and was not identified in 683 unrelated, unaffected individuals (Kleibl Z et al. Eur. J. Cancer. 2009 Mar;45:618-24). This variant has also been identified in an individual undergoing NGS panel testing who was diagnosed with breast cancer at age 37 (Tung N et al. Cancer. 2015 Jan;121:25-33). This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This variant was also reported in 4/60,466 breast cancer cases and in 7/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.