ClinVar Miner

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

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Total submissions: 8
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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
Invitae RCV000469959 SCV000550491 uncertain significance Familial cancer of breast 2020-09-26 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.
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.
Color Health, Inc RCV000130842 SCV000684616 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-23 criteria provided, single submitter clinical testing This missense variant replaces threonine with lysine at codon 59 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). A yeast-based complementation assay has shown that this variant protein partially impacts DNA damage response compared with wild type protein (PMID: 22419737). This variant has been reported in individuals affected with breast, colorectal, stomach, and ovarian cancer (PMID: 12052256). This variant has also been identified in 4/251456 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 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589927 SCV000889327 uncertain significance not provided 2017-09-27 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765626 SCV000896951 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
Ambry Genetics RCV000130842 SCV001173628 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-01 criteria provided, single submitter clinical testing The p.T59K variant (also known as c.176C>A), located in coding exon 1 of the CHEK2 gene, results from a C to A substitution at nucleotide position 176. The threonine at codon 59 is replaced by lysine, an amino acid with similar properties. In a large Icelandic study assessing breast tumors for loss of heterozygosity at the CHEK2 gene locus, this alteration was identified as a germline mutation in 9 individuals with cancer across 5 families, including individuals with breast, colon, ovarian, stomach, gastric, prostate and thyroid cancer. Some of these individuals had multiple primary cancers, and the youngest breast cancer diagnosis was at age 29. In total, this alteration segregated with cancer in 9 of 11 individuals with cancer across these 5 families. This alteration was absent in six individuals without a history of cancer in one of these families, and it was absent in 452 control subjects. Authors concluded that this may be a low penetrance cancer susceptibility allele (Ingvarsson S et al. Breast Cancer Res. 2002;4:R4). Another research group subsequently developed a yeast-based assay to assess in vivo CHEK2- mediated response to DNA damage and determined that this allele had an intermediate or partial loss of DNA damage response compared to that mediated by wild-type CHEK2 alleles (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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