Submissions for variant NM_007194.4(CHEK2):c.1036C>T (p.Arg346Cys)

gnomAD frequency: 0.00001  dbSNP: rs201206424

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131219	SCV000186171	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-12	criteria provided, single submitter	clinical testing	The p.R346C variant (also known as c.1036C>T), located in coding exon 9 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1036. The arginine at codon 346 is replaced by cysteine, an amino acid with highly dissimilar properties. In a study involving 42671 cases and 42164 controls, this variant was significantly associated with breast cancer [OR 5.06 (95% CI 1.09 to 23.5); p=0.017] (Southey MC et al. J. Med. Genet. 2016 Dec;53:800-811). In another study, this variant did not segregate with cancer in one family, but did show loss of heterozygosity in a tumor specimen (Grasel RS et al. Front Oncol, 2020 Oct;10:571330). This alteration has been identified in individuals diagnosed with breast cancer, ovarian cancer and mesothelioma (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6; Zheng Y et al. J Clin Oncol, 2018 Oct;36:2820-2825; Girard E et al. Int. J. Cancer, 2019 04;144:1962-1974; Hassan R et al. Proc Natl Acad Sci U S A, 2019 04;116:9008-9013; Krivokuca A et al. J. Hum. Genet., 2019 Apr;64:281-290; Apostolou P et al. Cancers (Basel), 2021 Apr;13:; Gomes R et al. Breast Cancer Res Treat, 2021 Feb;185:851-861). Additionally, 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 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 available evidence, the clinical significance of this alteration remains unclear.
GeneDx	RCV000212445	SCV000210979	uncertain significance	not provided	2023-09-22	criteria provided, single submitter	clinical testing	Observed in individuals with breast or ovarian cancer (Zheng et al., 2018; Girard et al., 2019; Krivokuca et al., 2019; Apostolou et al., 2021; Bhai et al., 2021; Fonfria et al., 2021; Gomes et al., 2021; Guindalini et al., 2022); Published functional studies demonstrate a damaging effect: reduced cell growth rate following DNA damage (Delimitsou et al., 2019); 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: 21244692, 26787654, 22114986, 28452373, 30287823, 31050813, 28580595, 30651582, 30303537, 33128190, 34204722, 33925588, 33134171, 27595995, 30851065, 33471991, 30975761, 22419737, 19782031, 36315097, 30130155, 34326862, 36978154, 35441217, 36243179, 35264596)
Invitae	RCV000232903	SCV000289640	uncertain significance	Familial cancer of breast	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 346 of the CHEK2 protein (p.Arg346Cys). This variant is present in population databases (rs201206424, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer (PMID: 21244692, 27595995, 30651582, 30851065, 33128190). ClinVar contains an entry for this variant (Variation ID: 142222). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065, 36468172). RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV000131219	SCV000684550	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 346 in the kinase 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). A functional study in human cells has shown the mutant protein to be defective in KAP1 phosphorylation and CHEK2 autophosphorylation (PMID: 37449874) and a study in yeast has shown the mutant protein to be defective in DNA damage response (PMID: 30851065). This variant has been reported individuals affected with breast cancer (PMID: 21244692, 30303537, 33128190, 33925588, 34204722), ovarian cancer (PMID: 30651582) and mesothelioma (PMID: 30975761), as well as in unaffected individuals (PMID: 30287823, 31214711, 32980694). This variant has been reported in four large breast cancer case-control studies or meta-analyses; reported in 23/73048 cases and 4/88658 unaffected controls (OR=5.85, 95%CI 2.00-16.92) (PMID: 37449874), 10/60466 cases and 2/53461 unaffected controls (OR=4.421, 95%CI 0.969-20.18) (PMID: 33471991; Leiden Open Variation Database DB-ID CHEK2_00011), 9/42671 cases and 2/42164 unaffected controls (OR=5.06. 95%CI 1.09-23.5) (PMID: 27595995), and 3/1313 cases and 0/1123 unaffected controls (OR=5.91, 95%CI 0.3051 to 114.5995) (PMID: 21244692). This variant has been identified in 13/251222 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.
Counsyl	RCV000232903	SCV000786015	uncertain significance	Familial cancer of breast	2018-02-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000232903	SCV000839468	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000764379	SCV000895414	uncertain significance	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate	2018-10-31	criteria provided, single submitter	clinical testing
Molecular Oncology Research Center, Barretos Cancer Hospital	RCV001374553	SCV001438680	uncertain significance	Hereditary breast ovarian cancer syndrome	2020-08-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000131219	SCV002537017	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-17	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465532	SCV002761102	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000232903	SCV004020170	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	RCV000232903	SCV004215850	uncertain significance	Familial cancer of breast	2023-10-30	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000212445	SCV004235061	uncertain significance	not provided	2023-05-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492617	SCV004240440	uncertain significance	Breast and/or ovarian cancer	2023-02-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002465532	SCV005076405	uncertain significance	not specified	2024-04-26	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1036C>T (p.Arg346Cys) 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 5.2e-05 in 251222 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Prostate Cancer (5.2e-05 vs 0.00025), allowing no conclusion about variant significance. c.1036C>T has been reported in the literature in individuals affected with various types of Cancer, including Breast cancer, Biliary tract cancer, Langer Hans Cell Histiocytosis and B-cell acute lymphoblastic leukemia (example, Guindalini_2022, Bhai_2021, Wagener_2022, Pereira_2022), and was also reported in the control cohorts from at-least two large case-control studies of cancer risk (example, Dorling_2021, Okawa_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Prostate Cancer and other CHEK2-related conditions. At least two publications report experimental evidence evaluating an impact on protein function. In a yeast growing assay, this variant significantly inhibit the normal growth of yeast (Delimitsou_2019), however in a subsequent study using an osteosarcoma cell line, this variant did not affect CHK2 function, as it resulted in comparable/slightly increased CHEK2 levels and was able to induce Phosphorylation of CHK2-Thr68 (Wagener_2022). The following publications have been ascertained in the context of this evaluation (PMID: 34326862, 30851065, 33471991, 35264596, 36243179, 35980532, 36468172). ClinVar contains an entry for this variant (Variation ID: 142222). Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355624	SCV001550560	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Arg346Cys variant was identified in 3 of 2606 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Le Calvez-Kelm 2011). The variant was also identified in dbSNP (ID: rs201206424) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Color Genomics, and Counsyl), and Cosmic (3x in breast, large intestine or lung tissue); it was not identified in MutDB or the Zhejiang University database. The variant was identified in control databases in 13 of 246016 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017) in the following populations: European in 10 of 111540 chromosomes (freq: 0.00009), Other in 1 of 5472 chromosomes (freq: 0.0002), East Asian in 1 of 17248 chromosomes (freq: 0.00006), and South Asian in 1 of 30776 chromosomes (freq: 0.00003); it was not observed in the African, Latino, Ashkenazi Jewish, or Finnish populations. The p.Arg346 residue is conserved across mammals and other organisms and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the 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, HumanSpliceFinder) do not predict a difference in splicing. 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000212445	SCV001906105	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212445	SCV001963414	likely pathogenic	not provided		no assertion criteria provided	clinical testing