ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1036C>T (p.Arg346Cys) (rs201206424)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131219 SCV000186171 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-03 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 one case-control study, this alteration was detected in 3/1303 breast cancer patients and 0/1109 healthy controls (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6). In another 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). This alteration was also identified in a Serbian cohort of 131 women with epithelial ovarian cancer (Krivokuca A et al. J. Hum. Genet., 2019 Apr;64:281-290) and in 1/1207 cases of French women with breast cancer who had a sister with breast cancer and were BRCA1 and BRCA2 negative and 0/1199 general population controls (Girard E et al. Int. J. Cancer, 2019 04;144:1962-1974). 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, 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 RCV000212445 SCV000210979 uncertain significance not provided 2019-08-02 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: reduced cell growth rate following DNA damage (Delimitsou 2019); This variant is associated with the following publications: (PMID: 30303537, 30651582, 28580595, 31050813, 30287823, 30851065, 28452373, 22114986, 27595995, 26787654, 21244692)
Invitae RCV000232903 SCV000289640 uncertain significance Familial cancer of breast 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 346 of the CHEK2 protein (p.Arg346Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs201206424, ExAC 0.008%). This variant has been observed in individuals affected with breast cancer (PMID: 21244692, 27595995, 30851065), ovarian cancer (PMID: 30651582) and prostate cancer (PMID: 27595995). ClinVar contains an entry for this variant (Variation ID: 142222). This variant has been reported to affect CHEK2 protein 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.
Color Health, Inc RCV000131219 SCV000684550 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-29 criteria provided, single submitter clinical testing
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 and ovarian cancer syndrome 2020-08-01 criteria provided, single submitter research
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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.