ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.980A>G (p.Tyr327Cys) (rs587780194)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212443 SCV000149945 uncertain significance not provided 2020-10-19 criteria provided, single submitter clinical testing Published functional studies are conflicting: reduced kinase activity, but DNA damage response and cell growth comparable to wild type (Delimitsou 2019, Kleiblova 2019); Observed in individuals with breast or prostate cancer, but also in unaffected controls (Dong 2003, Momozawa 2018, Kleiblova 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28201779, 12533788, 30287823, 30851065, 31050813)
Ambry Genetics RCV000116036 SCV000183857 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-11 criteria provided, single submitter clinical testing The p.Y327C variant (also known as c.980A>G), located in coding exon 8 of the CHEK2 gene, results from an A to G substitution at nucleotide position 980. The tyrosine at codon 327 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study looking at the prostate cancer risk associated with CHEK2 mutations, p.Y327C was detected in 1/400 males with sporadic prostate cancer, 0/298 affected males with familial prostate cancer and 0/423 unaffected male controls (Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80). 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.
Counsyl RCV000410273 SCV000489710 uncertain significance Familial cancer of breast 2016-11-11 criteria provided, single submitter clinical testing
Invitae RCV000410273 SCV000550462 uncertain significance Familial cancer of breast 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 327 of the CHEK2 protein (p.Tyr327Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs587780194, ExAC 0.006%). This variant has been observed in individuals affected with prostate cancer or breast cancer (PMID: 12533788, 31050813). ClinVar contains an entry for this variant (Variation ID: 128092). Experimental studies have shown this variant fails to phosphorylate KAP1 in human cells and results in reduced catalytic activity in vitro (PMID: 31050813). However, another study in yeast revealed this change has no effect on yeast strain growth and proliferation in response to DNA damage (PMID: 30851065). The clinical significance of these results is unknown. 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.
Fulgent Genetics,Fulgent Genetics RCV000515334 SCV000611457 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 RCV000116036 SCV000684703 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-01 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 327 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional impact of this variant on CHEK2 function is not clear, as one study in yeast has shown a neutral effect (PMID: 30851065), while another study in human cells reported a damaging effect (PMID: 31050813). This variant has been reported in an individual affected with breast cancer (PMID: 31050813) and in an individual affected with prostate cancer (PMID: 12533788). This variant has been identified in 4/251474 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV000410273 SCV001440946 uncertain significance Familial cancer of breast 2019-01-01 criteria provided, single submitter clinical testing
CZECANCA consortium RCV001270939 SCV001451743 likely pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000410273 SCV001553546 uncertain significance Familial cancer of breast no assertion criteria provided clinical testing The CHEK2 p.Tyr327Cys variant was identified in 1 of 800 proband chromosomes (frequency: 0.001) from an individual with sporadic prostate cancer and was not identified in 846 control chromosomes from healthy individuals or from 596 chromosomes from familial prostate cancer (Dong 2003). The variant was also identified in dbSNP (ID: rs587780194) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Gene Dx, Ambry Genetics, Counsyl, Invitae, Color and Fulgent Genetics). The variant was identified in control databases in 5 of 277198 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6468 chromosomes (freq: 0.0002), European Non-Finnish in 3 of 126694 chromosomes (freq: 0.00002), and South Asian in 1 of 30782 chromosomes (freq: 0.00003), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, or European Finnish populations. The p.Tyr327 residue is conserved in mammals but not in more distantly related organisms, and 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) 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000212443 SCV001739793 uncertain significance not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000212443 SCV001956578 uncertain significance not provided no assertion criteria provided clinical testing

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