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

gnomAD frequency: 0.00002  dbSNP: rs149991239

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000469959	SCV000550491	uncertain significance	Familial cancer of breast	2022-10-26	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 59 of the CHEK2 protein (p.Thr59Lys). This variant is present in population databases (rs149991239, gnomAD 0.004%). This missense change has been observed in individual(s) with breast, ovarian and colorectal cancer (PMID: 12052256). ClinVar contains an entry for this variant (Variation ID: 142041). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CHEK2 function (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	2022-07-15	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional study demonstrates reduction of DNA damage repair (Roeb et al., 2012); Observed in individuals with breast, colon, stomach, or ovarian cancer (Ingvarsson et al., 2002); This variant is associated with the following publications: (PMID: 15492928, 12610780, 23296741, 15385111, 16551709, 26506619, 16078115, 21807500, 15122511, 25467110, 18004398, 22058428, 21876083, 11719428, 28492532, 26206375, 14569133, 14568168, 16080966, 22114986, 11733767, 22419737, 12052256)
Color Diagnostics, LLC DBA Color Health	RCV000130842	SCV000684616	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-17	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	2022-07-15	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). In addition, 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. 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.
Baylor Genetics	RCV000469959	SCV004215854	uncertain significance	Familial cancer of breast	2023-11-06	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493455	SCV004242553	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing