Submissions for variant NM_007194.4(CHEK2):c.499G>A (p.Gly167Arg)

gnomAD frequency: 0.00001  dbSNP: rs72552322

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131700	SCV000186737	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-16	criteria provided, single submitter	clinical testing	The p.G167R variant (also known as c.499G>A), located in coding exon 3 of the CHEK2 gene, results from a G to A substitution at nucleotide position 499. The glycine at codon 167 is replaced by arginine, an amino acid with dissimilar properties. This alteration is located in the forkhead homology-associated domain, and based on internal structural analysis, it is anticipated to result in a significant decrease in structural stability (Li J et al. Mol. Cell. 2002 May;9:1045-54). This alteration has been reported in an ovarian cancer cohort, a male breast cancer patient, multiple prostate cancer patients, and in several ancestrally diverse cohorts of early-onset and/or familial breast cancer patients (Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Dufault MR et al. Int. J. Cancer. 2004 Jun;110:320–5; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Kraus C et al. Int J Cancer. 2017 Jan 1;140(1):95-102; Lolas Hamameh S et al. Int J Cancer. 2017 Aug 15;141(4):750-756; Carter NJ et al. Gynecol. Oncol., 2018 12;151:481-488; Fostira F et al. Breast Cancer Res. Treat. 2018 May;169(1):105-113; Wu Y et al. Prostate, 2018 06;78:607-615; Bernstein-Molho R et al. Breast Cancer Res. Treat., 2019 Jul;176:165-170; Fostira F et al. J. Med. Genet. 2019 Jul; Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9; Apostolou P et al. Cancers (Basel), 2021 Apr;13:). In one study, this variant was reported in 17/60,466 breast cancer cases and in 3/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). It was also seen in the homozygous state in two unrelated patients whose blood karyotypes exhibited multiple chromosomal translocations. The first patient had a history of several malignancies, including male breast cancer, prostate cancer, and renal cell carcinoma, and the second patient was diagnosed with acute myeloid leukemia at age 21 (Paperna T et al. J. Med. Genet. 2019). This alteration has been reported in an patient with a personal history of breast cancer diagnosed at age 42 who was also identified to carry a CHEK2 whole gene deletion (Stradella A et al. J. Med. Genet., 2019 08;56:521-525). In another study, this alteration was confirmed to be in trans with another CHEK2 variant in two sisters affected with breast cancer at 38 and 42 years, respectively. Authors determined this variant was inherited from the mother who died of non-Hodgkins lymphoma, while the other variant (p.I160M) was inherited from the father who had breast cancer. The p.G167R alteration was unable to grow after DNA damage in a yeast-based cell proliferation assay while the p.I160M variant showed normal or partial growth (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44; Delimitsou A et al. Hum. Mutat. 2019). This alteration was also reported as damaging in an mES cell-based assay of CHEK2 activity (Boonen RACM et al. Cancer Res, 2022 02;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. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000212424	SCV000210963	likely pathogenic	not provided	2023-09-07	criteria provided, single submitter	clinical testing	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; Also known as c.628G>A, p.(G210R); This variant is associated with the following publications: (PMID: 25525159, 27616075, 29520813, 30322717, 32805687, 22419737, 12533788, 27153395, 27751358, 26976419, 26681312, 15095295, 26845104, 25503501, 25428789, 28281021, 28301460, 28553140, 29335925, 28486781, 12049740, 29406849, 25186627, 29922827, 29522266, 30980208, 30851065, 30858171, 31159747, 31300551, 31296309, 31368036, 31398194, 32322110, 31220302, 19782031, 32658311, 32906215, 34426522, 33925588, 33558524, 34433815, 34903604, 33999380, 32900738, 25452411, 36119527, 35772246, 36061833, 36468172, 28888541, 35734982, 35418818, 36315097, 35127508, 34308104, 35220195, 32923877, 33471991, 30580288, 35892882)
Invitae	RCV000200030	SCV000254943	likely pathogenic	Familial cancer of breast	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 167 of the CHEK2 protein (p.Gly167Arg). This variant is present in population databases (rs72552322, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and/or prostate cancer (PMID: 12533788, 15095295, 22419737, 25452411, 25503501, 26976419, 27616075, 28888541, 30322717, 30980208, 31300551, 32805687, 32923877, 35220195, 35418818; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.628G>A, p.Gly210Arg. ClinVar contains an entry for this variant (Variation ID: 142524). 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: 22419737, 34903604, 36468172). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210071	SCV000266066	likely pathogenic	Breast and colorectal cancer, susceptibility to	2015-11-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212424	SCV000601171	likely pathogenic	not provided	2020-11-13	criteria provided, single submitter	clinical testing	This variant has been reported in individuals with breast cancer, male breast cancer, and prostate cancer in the published literature (PMID: 30851065 (2019), 29520813 (2018), 29335925 (2018), 28486781 (2017), 28281021 (2017), 27616075 (2016), 27153395 (2016), 26976419 (2016), 25503501 (2015), 15095295 (2004), 12533788 (2003)). The variant was reported homozygous due to consanguineous parentage in individuals with multiple primary cancers (PMID: 30858171 (2020), 29406849 (2018)), consistent with more severe presentation in bi-allelic CHEK2 carriers than in heterozygotes. In a yeast-based in vivo functional assay, the variant was shown to ablate CHEK2-mediated DNA damage repair response (PMID: 30851065 (2019), 22419737 (2012)). Taking into account the available information, we predict that the c.499G>A (p.Gly167Arg) variant is likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000212424	SCV000609074	likely pathogenic	not provided	2023-11-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131700	SCV000689693	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-30	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 167 in the FHA domain of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the variant results in a loss of DNA damage response in yeast-based assays (PMID: 22419737, 30851065), a decreased ability to phosphorylate KAP1 in CHEK2 knockout mouse embryonic stem cells (PMID: 34903604), and impaired CHEK2 autophosphorylation and KAP1 phosphorylation in a mammalian cell-based assay (PMID: 37449874). This variant has been reported in individuals affected with breast cancer (PMID: 15095295, 22419737, 25186627, 25452441, 25503501, 26976419, 27153395, 27616075, 28486781, 29335925, 29522266, 30580288, 30851065, 30858171, 31300551, 33925588, 35127508; Color internal data) and prostate cancer (PMID: 12533788, 29520813). This variant has been reported in two homozygous individuals affected with multiorgan tumorigenesis (PMID: 30858171) and has shown significant association with breast cancer in two large case-control meta-analyses (17/60449 cases and 3/53458 controls, OR=5.011, 95%CI 1.469 to 17.101, p-value=0.006; 11/73048 cases and 3/88658 controls, OR=4.09, 95%CI 1.08 to 22.81, p=0.03) (PMID: 33471991, 37449874). This variant has been identified in 6/251424 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV000212424	SCV000806883	likely pathogenic	not provided	2020-05-08	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000131700	SCV000821725	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-01-01	criteria provided, single submitter	clinical testing	This is a missense variant, substituting Glycine with Arginine in the position 167 of the CHEK2 protein. This particular glycine is highily conserved and located in a known functional domain (FHA - Forkhead-associated), while the physiochemical difference between Arginine and Glycine is high(Grantham Score 125). This finding has been reported in literature in breast cancer patients (PMID: 26976419 , PMID: 25503501) and in healthy individuals with family history of breast cancer (PMID: 26845104). The mutation database ClinVar contains entries for this variant (Variation ID: 142524/). The mutation is also present at low frequency in population databases (rs72552322, ExAC 0.006%). Furthermore, in silico and functional analysis indicate that the variant has an effect on the function or structure of the protein (PMID: 22419737 ).
Institute of Human Genetics, University of Leipzig Medical Center	RCV000200030	SCV001429385	likely pathogenic	Familial cancer of breast	2019-05-06	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212424	SCV002009494	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131700	SCV002537607	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-09-07	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291570	SCV002584545	likely pathogenic	Predisposition to cancer	2022-08-10	criteria provided, single submitter	clinical testing	The CHEK2 c.499G>A (p.Gly167Arg) missense change has a maximum subpopulation frequency of 0.0065% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant has been reported in individuals with breast cancer, ovarian cancer, and/or prostate cancer and has been found to segregate with familial disease (PMID: 12533788, 15095295, 22419737, 27153395, 27616075, 28888541, 30322717, 33558524). The in silico tool REVEL predicts a deleterious effect on protein function, and functional studies are in agreement with this prediction. This variant was characterized as damaging in a yeast-based assay evaluating DNA damage response (PMID: 22419737, 30851065). In summary, this variant meets criteria to be classified as likely pathogenic.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000200030	SCV003926642	likely pathogenic	Familial cancer of breast	2023-05-30	criteria provided, single submitter	clinical testing	a likely pathogenic variant was detected in the CHEK2 gene (c.499G>A). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 167 of the CHEK2 protein (p.Gly167Arg). This variant is present in population databases (rs72552322, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and/or prostate cancer (PMID: 12533788, 15095295, 22419737, 25452411, 25503501, 26976419, 27616075, 30322717, 30980208, 31300551). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142524). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 22419737). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Pathogenic/Likely pathogenic variants in the CHEK2 gene are associated with breast cancer susceptibility (OMIM# 114480).
Myriad Genetics, Inc.	RCV000200030	SCV004044123	likely pathogenic	Familial cancer of breast	2023-06-26	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000200030	SCV004217511	likely pathogenic	Familial cancer of breast	2023-10-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987371	SCV004803962	likely pathogenic	Malignant tumor of breast	2024-01-29	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.499G>A (p.Gly167Arg) results in a non-conservative amino acid change located in the forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 251424 control chromosomes (gnomAD). c.499G>A has been reported in the literature in multiple individuals affected with Breast Cancer, several of whom have strong family histories of breast cancer and/or other malignancies but where affected individuals were not available for genetic testing (e.g. Roeb_2012, Delimitsou_2019, Fostria_2020, Moradian_2021, Stolarova_2023). It has also been reported in individuals affected with prostate cancer (e.g. Dong_2003, Wu_2018), ovarian cancer (e.g. Carter_2018), and in the homozygous state in two unrelated individuals, one affected with multiple primary tumours and the other with early-onset leukaemia (Paperna_2020). There have also been reports of the variant in healthy controls or in unaffected family members, although in at least one case the individual was younger than the expected age of onset and in other cases the ages of these individuals were not always specified (e.g. Roeb_2012, Paperna_2020, Stolarova_2023). Multiple publications report experimental evidence evaluating an impact on protein function. Results from yeast-based assays (Roeb_2012, Delimitsou_2019), a mouse embryonic stem cell-based system (Boonen_2022), and CHEK2-complementation assays in human CHEK2-knockout cells (Stolarova_2023) all found the variant to be damaging, having no significant activity compared to negative controls. The following publications have been ascertained in the context of this evaluation (PMID: 34903604, 30322717, 30851065, 12533788, 31300551, 33558524, 30858171, 22419737, 37449874, 29520813). ClinVar contains an entry for this variant (Variation ID: 142524). Based on the evidence outlined above, the variant was classified as likely pathogenic.
True Health Diagnostics	RCV000131700	SCV000886682	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-11-09	no assertion criteria provided	clinical testing
Center of Medical Genetics and Primary Health Care	RCV000200030	SCV000987255	likely pathogenic	Familial cancer of breast	2020-04-08	no assertion criteria provided	research	ACMG Guidelines 2015 criteria The CHEK2 variant p.Gly167Arg was observed in the kinase domain in a tight region between amino acid 407-499 and in a mutation hotspot of 13 pathogenic variants (PM1 Pathogenic Moderate). One functional study (PMID: 22419737) confirmed its damaging effect (PS3 Pathogenic Strong). Meantime, an equivalent variant (chr22:29121058 C>G (Gly167Arg)) at the same amino acid residue is classified as pathogenic by UniProt (PS1 Pathogenic Strong). The allele frequency in GnomAD exomes is 0.0000239 which is less the threshold 0.0001 for recessive gene CHEK2, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). Meantime, majority of missense variants detected in CHEK2 are pathogenic and known cause of disease (PP2 Pathogenic Supporting). 10 pathogenic predictions from DANN, DEOGEN2, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationAssessor, MutationTaster, REVEL and SIFT versus 1 benign prediction from PrimateAI support its deleterious effect (PP3 Pathogenic Supporting). In our study the variant p.Gly167Arg was found in a 54-year-old female with family history of breast cancer. In summary, based on the evidence and given the previous reports of the variant in association with increased risk of breast cancer, we classified this variant as a Likely Pathogenic.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554290	SCV001774878	pathogenic	Breast carcinoma	2021-08-08	no assertion criteria provided	clinical testing