Submissions for variant NM_007194.4(CHEK2):c.1561C>T (p.Arg521Trp)

gnomAD frequency: 0.00003  dbSNP: rs533475838

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129111	SCV000183824	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-21	criteria provided, single submitter	clinical testing	The p.R521W variant (also known as c.1561C>T), located in coding exon 14 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1561. The arginine at codon 521 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been detected in breast cancer probands from Korea and Japan, but also has been seen in Japanese healthy control populations (Kim H et al. Breast Cancer Res. Treat. 2017 01;161(1):95-102; Momozowa Y et al. Nat Commun 2018 10;9(1):4083). 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). In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000656836	SCV000210997	uncertain significance	not provided	2024-06-10	criteria provided, single submitter	clinical testing	Observed in individuals with breast and/or ovarian cancer or biliary tract cancers, but also in healthy controls (PMID: 30287823, 28580595, 27783279, 34991090, 34326862, 36243179); Published functional studies are inconclusive: DNA damage response comparable to wild type in a yeast-based assay, intermediate to impaired kinase activity, and aberrant protein localization (PMID: 30851065, 34903604, 37449874); 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.1690C>T, p.(Arg564Trp); This variant is associated with the following publications: (PMID: 22090377, 27783279, 28580595, 30287823, 34426522, 34903604, 34991090, 32906215, 22419737, 37449874, 36243179, 34326862, 30851065)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230444	SCV000289668	uncertain significance	Familial cancer of breast	2024-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 521 of the CHEK2 protein (p.Arg521Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 27783279, 28580595, 30287823, 32068069, 34903604, 34991090). This variant is also known as c.1690C>T (p.Arg564Trp). ClinVar contains an entry for this variant (Variation ID: 140881). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 30851065). 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.
Counsyl	RCV000230444	SCV000488455	uncertain significance	Familial cancer of breast	2016-03-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129111	SCV000537597	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 521 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have shown this variant to be neutral in yeast-based DNA damage repair assay (PMID: 30851065) but to have an intermediate level of function in a mouse embryonic stem cell-based Kap1 phosphorylation assay (PMID: 34903604). This variant has been reported in individuals affected with breast, pancreatic, and colorectal cancer, but also in control individuals (PMID: 27783279, 28580595, 30287823, 32980694, 33309985, 33471991, 34991090, 37449874). This variant has been identified in 14/264616 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656836	SCV000889325	uncertain significance	not provided	2019-04-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192414	SCV001360509	uncertain significance	not specified	2022-06-30	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1561C>T (p.Arg521Trp) results in a non-conservative amino acid change in 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 0.00028 in 309214 control chromosomes, predominantly at a frequency of 0.00044 within the East Asian subpopulation in the gnomAD database. This frequency is slightly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (0.00044 vs 0.00031), suggesting this variant may be benign. c.1561C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One study combined 30 population-based and 14 family-based studies and showed that this variant is not associated with breast cancer (OR=2.48, p=0.0819). At least two publications report experimental evidence evaluating an impact on protein function and showed that this variant has no or intermediate effect on protein function (Delimitsou_2019, Boonen_2022). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Genetic Services Laboratory, University of Chicago	RCV001192414	SCV002067803	uncertain significance	not specified	2019-11-13	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000230444	SCV002581877	uncertain significance	Familial cancer of breast	2022-09-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000230444	SCV004020208	uncertain significance	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000230444	SCV004217651	uncertain significance	Familial cancer of breast	2024-02-28	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492584	SCV004240449	uncertain significance	Breast and/or ovarian cancer	2023-04-26	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354094	SCV001548623	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Arg521Trp variant was identified in 5 of 11648 proband chromosomes (frequency: 0.0004) from German and Korean individuals or families with breast cancer (including BRCA1/2-negative cases; Hauke 2018, Kim 2017). The variant was also identified in dbSNP (ID: rs533475838) as “With Likely benign, Uncertain significance allele” and ClinVar (classified uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Color and Quest Diagnostics Nichols Institute San Juan Capistrano). The variant was identified in control databases in 14 of 259842 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 22546 chromosomes (freq: 0.00004), European in 5 of 121862 chromosomes (freq: 0.00004), and East Asian in 8 of 18540 chromosomes (freq: 0.0004), while it was not observed in the Other, Latino, Ashkenazi Jewish, Finnish, or South Asian populations. The p.Arg521 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Trp variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. One computational study suggested that the variant could have resulted from an interlocus gene conversion event (Cassola 2012). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.