Submissions for variant NM_007194.4(CHEK2):c.663C>G (p.Ile221Met)

gnomAD frequency: 0.00027  dbSNP: rs200451612

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131415	SCV000186393	likely benign	Hereditary cancer-predisposing syndrome	2020-07-21	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000588152	SCV000210969	uncertain significance	not provided	2024-08-12	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204676	SCV000261064	uncertain significance	Familial cancer of breast	2024-01-29	criteria provided, single submitter	clinical testing	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.
Color Diagnostics, LLC DBA Color Health	RCV000131415	SCV000684676	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-08	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330506	SCV000698813	likely benign	not specified	2023-08-21	criteria provided, single submitter	clinical testing	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 6.1e-05 in 262462 control chromosomes (gnomAD, Le Calves-Kelm_2011), predominantly at a frequency of 0.00052 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (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 (Le Calvez-Kelm 2011). Experimental evidence from a yeast complementation assay indicated that the variant did not have a damaging effect on protein function (Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 21244692, 27720647, 26787654, 30851065). Nine ClinVar submitters have assessed the variant since 2014: seven classified the variant as uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000204676	SCV000785252	uncertain significance	Familial cancer of breast	2017-06-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588152	SCV000888118	uncertain significance	not provided	2023-03-31	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00052 (12/22912 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMIDs: 21244692 (2011), 27153395 (2016), 32936981 (2021)). A functional assay in yeast showed that this CHEK2 variant protein maintains DNA repair function (PMID: 30851065 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001543106	SCV001761613	likely benign	Predisposition to cancer	2023-09-14	criteria provided, single submitter	clinical testing	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.
Sema4, Sema4	RCV000131415	SCV002537629	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-23	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000204676	SCV004020215	likely benign	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	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].
Baylor Genetics	RCV000204676	SCV004215844	uncertain significance	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV004556746	SCV004228988	not provided	CHEK2-related cancer predisposition		no assertion provided	phenotyping only	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.
PreventionGenetics, part of Exact Sciences	RCV004737224	SCV005364923	uncertain significance	CHEK2-related disorder	2024-09-06	no assertion criteria provided	clinical testing	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.