ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1216C>T (p.Arg406Cys) (rs587782527)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131715 SCV000186753 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-11 criteria provided, single submitter clinical testing The p.R406C variant (also known as c.1216C>T), located in coding exon 10 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1216. The arginine at codon 406 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with a personal and/or family history of breast cancer (Osorio A et al. Int. J. Cancer. 2004 Jan;108:54-6; Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6), as well as individuals with ovarian cancer, prostate cancer, and sarcoma (Rashid MU et al. BMC Cancer. 2013 Jun;13:312; Ballinger ML et al. Lancet Oncol. 2016 Sep;17:1261-71; Isaacsson Velho P et al. Prostate. 2018 Apr;78:401-407). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000587346 SCV000210986 uncertain significance not provided 2021-06-02 criteria provided, single submitter clinical testing Published functional studies demonstrate no damaging effect: similar growth rates to the wild-type in a yeast-based assay (Delimitsou 2019); Observed in individuals with a personal or family history of sarcoma, breast, or ovarian cancer (Osorio 2004, Le Calvez-Kelm 2011, Rashid 2013, Ballinger 2016, Girard 2019); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as CHEK2 c.1345C>T (p.Arg449Cys); This variant is associated with the following publications: (PMID: 26787654, 23741719, 28514183, 28553140, 25629968, 23806170, 14618615, 27498913, 21244692, 29173497, 28102005, 29368341, 29596542, 30851065, 19782031, 22419737, 27535533, 30303537, 32322110)
Invitae RCV000228975 SCV000289656 uncertain significance Familial cancer of breast 2020-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 406 of the CHEK2 protein (p.Arg406Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587782527, ExAC 0.006%). This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 14618615, 23806170, 21244692) as well as prostate cancer (PMID: 29368341). ClinVar contains an entry for this variant (Variation ID: 142533). This variant has been reported not to substantially 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.
Counsyl RCV000228975 SCV000488796 uncertain significance Familial cancer of breast 2016-06-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515410 SCV000611449 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131715 SCV000684570 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-29 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 406 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). A functional study has reported this variant protein as benign in a yeast complementation assay (PMID: 30851065). This variant has been reported in individuals with personal and/or family history of breast and ovarian cancer (PMID: 14618615, 21244692, 23806170) and prostate cancer (PMID: 29368341). This variant has also been identified in 17/282232 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855593 SCV000698764 likely benign not specified 2021-02-25 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1216C>T (p.Arg406Cys) results in a non-conservative amino acid change located in the Protein kinase domain(IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.1e-05 in 254176 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer Syndrome (5.1e-05 vs 0.00031), allowing no conclusion about variant significance. The variant, c.1216C>T has been reported in the literature in an individual with moderate risk for Breast Cancer (BrC) and/or Ovarian Cancer (OC) and in patients with BrC, OC or Prostate Cancer (Calvez-Kelm_2011, Rashid_2013, Osorio_2004, Isaacsson_2018 , Koczkowska_2018, Girard_2019). In a yeast functional study, the variant was found to be benign (Delimitsou_2019). Co-occurrences with other pathogenic variants have been reported by our laboratory (BRCA1 c.1326T>A, p.Cys442X; BRCA2 c.6468_6469delTC, p.Q2157fs*18), further providing supporting evidence for a benign role. Eight other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. We have previously classified this variant as a VUS-possibly benign. However, after an extensive review of literature spanning 8 years (2011-2019) no compelling evidence supporting a pathogenic outcome has been ascertained. Therefore, the variant has been classified as likely benign.
Mendelics RCV000228975 SCV000839463 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287137 SCV001473787 uncertain significance none provided 2020-01-01 criteria provided, single submitter clinical testing The CHEK2 c.1216C>T; p.Arg406Cys variant (rs587782527) is reported in the literature in individuals with breast, ovarian, or prostate cancer (Isaacsson 2018, Le Calvez-Kelm 2011, Osorio 2004, Rashid 2013), and is reported in ClinVar (Variation ID: 142533). This variant is found in the general population with an overall allele frequency of 0.006% (17/282232 alleles) in the Genome Aggregation Database. The arginine at codon 406 is moderately conserved, but computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Additionally, an in vivo yeast-based functional assay suggests that this variant is benign (Delimitsou 2019). However, due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Delimitsou A et al. Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Hum Mutat. 2019 May;40(5):631-648. Isaacsson Velho P et al. Intraductal/ductal histology and lymphovascular invasion are associated with germline DNA-repair gene mutations in prostate cancer. Prostate. 2018 Apr;78(5):401-407. Le Calvez-Kelm F et al. Rare, evolutionarily unlikely missense substitutions in CHEK2 contribute to breast cancer susceptibility: results from a breast cancer family registry case-control mutation-screening study. Breast Cancer Res. 2011 Jan 18;13(1):R6. Osorio A et al. The breast cancer low-penetrance allele 1100delC in the CHEK2 gene is not present in Spanish familial breast cancer population. Int J Cancer. 2004 Jan 1;108(1):54-6. Rashid MU et al. Constitutional CHEK2 mutations are infrequent in early-onset and familial breast/ovarian cancer patients from Pakistan. BMC Cancer. 2013 Jun 27;13:312.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356488 SCV001551673 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 p.Arg406Cys variant was identified in 1 of 290 proband chromosomes (frequency: 0.003) from Pakistani individuals or families with BRCA1/2 negative early-onset and familial breast/ovarian cancers and was not identified in 300 control chromosomes from healthy individuals, or 229 individuals with BRCA1/2 negative breast/ovarian cancers (Rashid 2013). In a yeast complementation assay assessing protein function of the Arg406His variant, the variant did not abrogate CHEK2 function, with yeast cells carrying the Arg406His variant growing at a similar rate to those carrying wildtype (Yilmaz 2014). The variant was also identified in in dbSNP (ID: rs587782527) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry genetics, GeneDx, Invitae, and Counsyl), Clinvitae; and in control databases in 17 of 276708 chromosomes at a frequency of 0.00006 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The p.Arg406 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Cys 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.

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