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

gnomAD frequency: 0.00002  dbSNP: rs149991239

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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	2023-11-14	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 (PMID: 22419737); Observed in individuals with breast, colon, stomach, or ovarian cancer (PMID: 12052256); 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	RCV003493455	SCV000698791	uncertain significance	not specified	2025-02-19	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.176C>A (p.Thr59Lys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 252360 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.176C>A has been reported in the literature in individuals affected with breast, ovarian or colorectal cancer as well as unaffected controls (Ingvarsson_2002, Dorling_2021, Stolarova_2023). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Publications report experimental evidence evaluating an impact on protein function, finding either an intermediary or wild type function (Roeb_2012, Stolarova_2023). The following publications have been ascertained in the context of this evaluation (PMID: 12052256, 22419737, 26206375, 33471991, 37449874). ClinVar contains an entry for this variant (Variation ID: 142041). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589927	SCV000889327	uncertain significance	not provided	2024-06-25	criteria provided, single submitter	clinical testing	The CHEK2 c.176C>A (p.Thr59Lys) variant has been reported in the published literature in individuals with breast cancer (PMID: 28779002 (2017), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)) and in cohort of individuals with breast, colorectal, stomach, or ovarian cancer (PMID: 12052256 (2002)). This variant has also been identified in reportedly healthy individuals (PMID: 28779002 (2017), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/CHEK2)). A yeast based functional study reported that this variant displays an intermediate response to DNA damage (PMID: 22419737 (2012)). The frequency of this variant in the general population, 0.000035 (4/113734 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
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	2024-09-24	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. Based on the available evidence, the clinical significance of this variant 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	2025-03-04	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000589927	SCV005410222	uncertain significance	not provided	2024-05-02	criteria provided, single submitter	clinical testing	PM2
Fulgent Genetics, Fulgent Genetics	RCV005025213	SCV005663145	uncertain significance	Li-Fraumeni syndrome 2; Bone osteosarcoma; Familial prostate cancer	2024-05-13	criteria provided, single submitter	clinical testing