ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs201206424
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Total submissions: 17
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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
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

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