ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1312G>T (p.Asp438Tyr) (rs200050883)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115996 SCV000172942 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000587890 SCV000892301 uncertain significance not provided 2018-09-30 criteria provided, single submitter clinical testing
Color RCV000115996 SCV000537526 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-13 criteria provided, single submitter clinical testing
Counsyl RCV000199565 SCV000489071 uncertain significance Familial cancer of breast 2016-08-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515311 SCV000611451 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000587890 SCV000149905 uncertain significance not provided 2018-10-04 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1312G>T at the cDNA level, p.Asp438Tyr (D438Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAT>TAT). This variant, also denoted c.1441G>T and p.Asp481Tyr using an alternate reference sequence (NP_001005735.1), has been observed in individuals with a history of breast, prostate, colorectal, or endometrial cancer, as well as in healthy controls (Seppala 2003, Bell 2007, Tischkowitz 2008, Le Calvez-Kelm 2011, Baloch 2014, Tung 2015, Ring 2016, Kayser 2018). No statistically significant association with breast cancer has been identified; however, evidence of a weak association with prostate cancer has been reported (Southey 2016). CHEK2 Asp438Tyr was shown to exhibit a 70% reduction in kinase activity in a cell-based assay when compared to wild-type CHEK2 (Bell 2007). However, it is unclear whether such a reduction in kinase activity would be sufficient to contribute to cancer risk. Although this variant was observed in large population cohorts, population data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). CHEK2 Asp438Tyr is located within the protein kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Asp438Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000115996 SCV000821989 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
GenomeConnect, ClinGen RCV000587890 SCV000986776 not provided not provided no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported, most recently, on 12/04/2018 by GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Integrated Genetics/Laboratory Corporation of America RCV000587890 SCV000698770 uncertain significance not provided 2017-08-09 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.1312G>T (p.Asp438Tyr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 37/128758 control chromosomes including ExAC at a frequency of 0.0002874. The allele frequencies of this variant in European (Finnish) and European (Non-Finnish) subpopulations are slightly higher than the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284), suggesting this variant is likely a benign polymorphism. The variant has been reported in breast, ovarian and prostate cancer patients in the literature, without strong evidence for causality. In support of a benign role of the variant, one patient also carried a pathogenic MSH2 variant in addition to the variant of interest (Ring_2016). However, one case-control study reported a significant association with prostate cancer (odds ratio: 2; 95% CI 1.06 to 4.63; p=0.030), while the variant was not associated with breast cancer risk (Le Calvez-Kelm_2011, Southey_2016). In one HBOC family, while one affected member carried this variant, another affected did not and authors classified this variant as likely benign (Maxwell_2016). Additionally, one functional study reported the variant to result in 70% reduced BRCA1 phosphorylation in a cell-based assay (Bell_2007), suggesting the variant may have a functional impact. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Based on the currently available evidences, this variant has been classified as a Variant of Unknown Significance.
Invitae RCV000199565 SCV000254923 likely benign Familial cancer of breast 2018-01-08 criteria provided, single submitter clinical testing
Mendelics RCV000199565 SCV000839460 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
PreventionGenetics RCV000587890 SCV000806866 uncertain significance not provided 2017-08-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000200982 SCV000601150 uncertain significance not specified 2017-05-05 criteria provided, single submitter clinical testing

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