ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.176C>A (p.Thr59Lys) (rs149991239)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622258 SCV000185740 uncertain significance Inborn genetic diseases 2014-06-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Color RCV000130842 SCV000684616 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-15 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765626 SCV000896951 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000589927 SCV000568302 uncertain significance not provided 2018-10-22 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.176C>A at the cDNA level, p.Thr59Lys (T59K) at the protein level, and results in the change of a Threonine to a Lysine (ACA>AAA). This variant was observed in individuals with breast, colon, stomach, or ovarian cancer (Ingvarsson 2002). While the majority of the tumors tested by Ingvarsson (2002) showed loss of heterozygosity, CHEK2 Thr59Lys did not segregate with disease in two families with familial cancer (Ingvarsson 2002). In vivo assays demonstrated reduction in DNA damage response (Roeb 2012). CHEK2 Thr59Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Threonine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. CHEK2 Thr59Lys is located in the FHA 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 Thr59Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589927 SCV000698791 uncertain significance not provided 2015-11-26 criteria provided, single submitter clinical testing Variant summary: This c.176C>A variant affects a conserved nucleotide, resulting in non-conservative amino acid change from Thr to Lys. 4/4 in-silico tools predict this variant to be damaging. This variant was found in 2/50644 control chromosomes for a frequency of 0.0000395, which slightly exceeds the maximal expected frequency of a pathogenic allele (0.0000284) in this gene based on the disease prevalence of LFS. However, there are only two variant occurrences and this may not rule out the chance finding. In addition, low frequency coupled with only two variant occurrences may also indicate that the variant carriers might represent as subclinical cases or reduced penetrance. This assumption is also supported by its occurrence in cancer patients. The variant has been reported in multiple cancer families with spectrum of cancers (familial and sporadic breast cancer, stomach cancer, thyroid cancer, colorectal cancer, ovarian cancer and prostate cancer) (Ingvarsson 2002). However, the available family data does not strongly indicate a positive or a lack of cosegregation with the disease. It is not specified in the publication whether the families with this variant fulfilled the diagnostic criteria for LFS. One yeast-based in vivo functional assay showed a decrease in DNA damage response by this variant; however, the finding was not sufficient to strongly infer the pathogenicity. LOH analysis in tumor samples was consistent with a possible pathogenic outcome. One clinical laboratory has classified this variant as having uncertain significance. Taken together, this variant has currently been classified as a Variant of Uncertain Significance.
Invitae RCV000469959 SCV000550491 uncertain significance Familial cancer of breast 2018-12-18 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 59 of the CHEK2 protein (p.Thr59Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is present in population databases (rs149991239, ExAC 0.001%). This variant has been reported in individuals affected with breast, ovarian and colorectal cancer (PMID: 12052256). ClinVar contains an entry for this variant (Variation ID: 142041). Experimental studies in yeast have shown that this missense change reduces the function of CHEK2 to a similar extent as other partially damaging alleles (PMID: 22419737). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589927 SCV000889327 uncertain significance not provided 2017-09-27 criteria provided, single submitter clinical testing

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