ClinVar Genomic variation as it relates to human health

The CHEK2 c.663C>G (p.Ile221Met) missense change has a maximum subpopulation frequency of 0.052% in gnomAD v2.1.1 and a maximum subpopulation frequency of 0.096% in gnomAD v3.2.1. The in silico tool REVEL predicts a benign effect on protein function and functional studies are in agreement with this prediction. A yeast-based growth assay indicated that this variant behaved similar to the wild-type (PMID: 30851065) and CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells also indicated that this variant behaved similar to wild-type (PMID: 37449874). Although this variant has been reported in an individual diagnosed with breast cancer prior to age 45 (PMID: 21244692), seven individuals with this variant are reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com). In summary, this variant meets criteria to be classified as likely benign.

This missense variant replaces isoleucine with methionine at codon 221 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). A functional study has shown this variant to have neutral effect on CHEK2 protein function in a DNA damage repair assay in yeast (PMID: 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 21244692, 32936981). This variant has also been identified in 16/260244 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in seven females over age 70 who lack personal history of cancer (FLOSSIES, https://whi.color.com/variant/22-29115403-G-C). 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 sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 221 of the CHEK2 protein (p.Ile221Met). This variant is present in population databases (rs200451612, gnomAD 0.05%), 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). ClinVar contains an entry for this variant (Variation ID: 142342). 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. 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.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27720647, 19782031, 21244692, 26787654, 27153395, 32936981, 22419737, 37449874, 30851065, 32832836)

Variant summary: CHEK2 c.663C>G (p.Ile221Met) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 231092 control chromosomes (gnomAD, Le Calves-Kelm_2011), predominantly at a frequency of 0.00049 within the African or African-American subpopulation in the gnomAD database, which is approximately 2.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031). Additionally, the variant was reported in 6/2559 African American women (carrier frequency of 0.002345), who were older than 70 years of age with no personal history of cancer (FLOSSIES database). These data suggest that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.663C>G has been reported in the literature in one individual affected with Breast Cancer, without evidence for causality (e.g. Le Calvez-Kelm 2011). Experimental evidence from a yeast complementation assay (Delimitsou_2019), CHEK2-complementation assay, and KAP1 phosphorylation assays (Stolarova_2023) indicated that the variant did not have a damaging effect on protein function. The following publications have been ascertained in the context of this evaluation (PMID: 30851065, 21244692, 27720647, 37449874, 26787654). ClinVar contains an entry for this variant (Variation ID: 142342). Based on the evidence outlined above, the variant was classified as likely benign.

The CHEK2 c.663C>G (p.Ile221Met) variant has been reported in the published literature in individuals with a personal and/or family history of breast/ovarian cancer (PMIDs: 21244692 (2011), 27153395 (2016), 32936981 (2021)). Functional studies reported this variant to have no damaging effect on CHEK2 function (PMIDs: 30851065 (2019), 37449874 (2023)). The frequency of this variant in the general population, 0.00052 (12/22912 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant.

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].

The CHEK2 c.-1C>G variant is located in the 5' untranslated region. This variant has been identified in 4 individuals with breast and/or ovarian cancer (Supplementary Table 1, Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Table S4, Maxwell et al. 2016. PubMed ID: 27153395). Functional assessment using a combination of silico tools produced conflicting results, however assessment using a yeast functional assay suggested this variant is benign (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). This variant has been observed with a subpopulation frequency of 0.05% in the gnomAD database, which may be too common to be a primary cause of disease. This variant is classified in ClinVar as uncertain significance (7) and likely benign (4) (https://www.ncbi.nlm.nih.gov/clinvar/variation/142342/). Although, we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. 

Variant interpreted as Uncertain significance and reported on 11-01-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.