ClinVar Genomic variation as it relates to human health

Variant summary: CHEK2 c.751A>T (p.Ile251Phe) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 255478 control chromosomes (gnomAD, and publication data). c.751A>T has been reported in the literature in individuals undergoing multigene panel testing within settings of breast cancer (e.g. Desrichard_2011, Young_2016, Hauke_2018, Dorling_2021), in a family with prostate cancer where this variant did not segregate with disease among two genotyped affected family members (Dong_2003), and in individuals with colorectal cancers (Yurgelun_2015, Yurgelun_2017, Pearlman_2016). At least one co-occurrence with another pathogenic variant has been reported in a female with MMR proficient colorectal cancer (BRCA2 c.1755_1759del, p.K585Nfs*3, Pearlman_2016), providing supporting evidence for a benign role. These data do not allow clear conclusions about variant significance. At least two functional studies reported experimental evidence evaluating an impact on protein function, and assigned a "damaging" functional classification in a yeast-based functional assay evaluating the DNA repair-ability after chemically induced DNA damage (Delimitsou_2019), while another study reported moderately reduced autophosphorylation, with severely reduced (~15%) kinase activity toward the phosphorylation of target protein KAP1 in a CHEK2 knockout mouse embryonic stem cell system (Boonen_2022). Nine ClinVar submitters have assessed this variant since 2014: all submitters classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

This missense variant replaces isoleucine with phenylalanine at codon 251 of the CHEK2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have reported the mutant protein to be non-functional in a yeast complementation assay (PMID: 30851065) and to show impaired kinase activity toward a downstream target protein Kap1 despite intact auto-phosphorylation (PMID: 34903604). This variant has been reported in individuals affected with breast cancer (PMID: 22114986, 29522266; Color internal data), colorectal cancer (PMID: 27978560), suspected Lynch syndrome (PMID: 25980754) and prostate cancer (PMID 12533788). Some of these affected individuals also carried a pathogenic variant in a different gene that could explain the observed phenotype (PMID: 2797856; Color internal data). This variant has also been observed in an unaffected control individual (PMID: 21244692). This variant has been identified in 5/282756 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 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 isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 251 of the CHEK2 protein (p.Ile251Phe). This variant is present in population databases (rs587780189, gnomAD 0.03%). This missense change has been observed in individual(s) with prostate cancer and breast cancer (PMID: 12533788, 22114986, 25980754, 27978560). ClinVar contains an entry for this variant (Variation ID: 128086). 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 affects CHEK2 function (PMID: 30851065, 34903604). 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.I251F variant (also known as c.751A>T), located in coding exon 5 of the CHEK2 gene, results from an A to T substitution at nucleotide position 751. The isoleucine at codon 251 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration is located in the CHK2 kinase domain and has been detected in cohorts of individuals with hereditary breast cancer, colorectal cancer younger than 50 years, sarcoma, as well as familial prostate cancer (Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Desrichard A et al. Breast Cancer Res. 2011;13:R119; Ballinger ML et al. Lancet Oncol. 2016 Sep;17:1261-71; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471; Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358). In one case-control study, this alteration was not detected in 1313 breast cancer patients diagnosed at or before age 45, but it was seen in 1/1123 healthy controls (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6). This alteration behaved as non-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 damaging in an mES cell-based assay of CHEK2 activity (Boonen RACM et al. Cancer Res, 2022 Feb;82:615-631). 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.

Observed in individuals with a personal or family history of breast, prostate, colorectal, or other cancers, as well as in healthy controls (PMID: 12533788, 22114986, 21244692, 25980754, 27498913, 27978560, 28135145, 29522266, 33471991, 34326862); Published functional studies are inconclusive: demonstrates intermediate impact on auto-phosphorylation, impaired kinase activity against KAP1, and showed reduced response to DNA damage in a yeast-based assay (PMID: 30851065, 34903604, 37449874); Also known as c.880A>T, p.(I294F); 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; This variant is associated with the following publications: (PMID: 31398194, 12533788, 22114986, 25980754, 26787654, 27978560, 21244692, 28135145, 27498913, 29596542, 29522266, 28843361, 30851065, 34903604, 33471991, 35127508, 35441217, 22419737, 19782031, 37449874, 34326862)