Submissions for variant NM_007194.4(CHEK2):c.-4C>T

gnomAD frequency: 0.00014  dbSNP: rs374938148

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589024	SCV000149886	uncertain significance	not provided	2024-12-23	criteria provided, single submitter	clinical testing	Observed in individuals with breast, ovarian, or pancreatic cancer (PMID: 17145815, 28779002, 29522266, 31784482, 34326862, 34371384, 35264596, 35534704, 35886069); Not observed at significant frequency in large population cohorts (gnomAD); Nucleotide is not conserved across species and the substitution has no predicted effect on splicing; Describes a nucleotide substitution 4 base pairs upstream of the ATG translational start site of the CHEK2 gene, occurring in the consensus Kozak sequence, the nucleotides just upstream of the ATG start codon, which play a major role in the initiation of translation; This variant is associated with the following publications: (PMID: 31784482, 17145815, 28779002, 21681852, 29522266, 35886069, 34371384, 35264596, 35896598, 34326862, 35534704)
Ambry Genetics	RCV000115977	SCV000215929	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-25	criteria provided, single submitter	clinical testing	The c.-4C>T variant is located in the 5' untranslated region (5’ UTR) of the CHEK2 gene. This variant results from a C to T substitution 4 bases upstream from the first translated codon. This variant has been reported in a woman with ovarian cancer whose tumor showed loss of heterozygosity at the CHEK2 locus (Williams LH et al. Clin. Cancer Res. 2006 Dec;12:6967-72). 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 nucleotide position is not well conserved in available vertebrate species. This alteration is predicted to slightly decrease the efficiency of the native splice acceptor site by the BDGP and ESEfinder in silico models. RNA studies have demonstrated this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232150	SCV000289637	uncertain significance	Familial cancer of breast	2024-07-22	criteria provided, single submitter	clinical testing	This variant occurs in a non-coding region of the CHEK2 gene. It does not change the encoded amino acid sequence of the CHEK2 protein. This variant is present in population databases (rs374938148, gnomAD 0.01%). This variant has been observed in individual(s) with CHEK2-related conditions (PMID: 4326862, 17145815, 28779002, 35264596, 35886069). ClinVar contains an entry for this variant (Variation ID: 128039). 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.
Counsyl	RCV000232150	SCV000489336	uncertain significance	Familial cancer of breast	2016-09-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001175353	SCV000698808	uncertain significance	not specified	2024-05-06	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.-4C>T is located in the untranslated mRNA region upstream of the initiation codon. This variant lies within the Kozak sequence, a region that plays a role in the initiation of translation. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. The variant allele was found at a frequency of 5.7e-05 in 244790 control chromosomes. The observed variant frequency is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Li-Fraumeni Syndrome phenotype (2.8e-05), strongly suggesting that the variant is benign. c.-4C>T has been reported in the literature in individuals affected with breast cancer (e.g. Decker_2017, Paduano_2022, Guindalini_2022) or unspecified breast/ovarian or pancreatic cancer (e.g. Bono_2021), both without evidence of causality, in chronic myeloid leukemia with other reportedly causative variants (e.g. Kazemi-Sefat_2022), and in ovarian cancer with tumor loss of heterozygosity and faint protein expression by IHC, suggesting a potential role of the variant in tumorigenesis (e.g.Williams_2006). These reports do not provide unequivocal conclusions about association of the variant with Li-Fraumeni Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MLH1 c.1517T>C, p.V506A), providing supporting evidence for a benign role. The following publications have been ascertained in the context of this evaluation (PMID: 34371384, 28779002, 35264596, 35896598, 35886069, 17145815, 21681852). ClinVar contains an entry for this variant (Variation ID: 128039). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mendelics	RCV000232150	SCV000839508	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115977	SCV000902801	likely benign	Hereditary cancer-predisposing syndrome	2016-10-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115977	SCV002537608	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000232150	SCV004044104	uncertain significance	Familial cancer of breast	2023-05-08	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001175353	SCV004242578	uncertain significance	not specified	2025-03-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589024	SCV005625256	uncertain significance	not provided	2024-11-29	criteria provided, single submitter	clinical testing	The CHEK2 c.-4C>T variant has been reported in the published literature in individuals with breast cancer (PMIDs: 28779002 (2017), 35886069 (2022), 35534704 (2022), and 35264596 (2022)), in an individual with unspecified breast/ovarian or pancreatic cancer (PMID: 34371384 (2021)), in chronic myeloid leukemia with a causative variant in another gene (PMID: 35896598 (2022)), and an individual with ovarian cancer whose tumor showed loss of heterozygosity and low protein expression by immunohistochemistry (PMID: 17145815 (2006)). The frequency of this variant in the general population, 0.00011 (12/107708 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect CHEK2 mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115977	SCV005688918	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-10	criteria provided, single submitter	clinical testing	The splice region variant NM_001005735.2(CHEK2):c.-4C>T has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.-4C>T variant is not predicted to disrupt the existing acceptor splice site 3bp upstream by any splice site algorithm. The c.-4C>T variant is not predicted to introduce a novel splice site by any splice site algorithm. For these reasons, this variant has been classified as Uncertain Significance
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356669	SCV001551903	uncertain significance	Familial ovarian cancer		no assertion criteria provided	clinical testing	The CHEK2 c.-4C>T variant was identified in 1 of 238 proband chromosomes (frequency: 0.004) from individuals or families with ovarian cancer and was not identified in 516 control chromosomes from healthy individuals (Williams 2006). The variant was also identified in dbSNP (ID: rs374938148) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Counsyl, and Integrated Genetics/Laboratory Corporation of America). The variant was not identified in Cosmic, or Zhejiang University databases. The variant was identified in control databases in 15 of 238966 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 14970 chromosomes (freq: 0.00007), European in 13 of 105550 chromosomes (freq: 0.0001), and South Asian in 1 of 30676 chromosomes (freq: 0.00003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The c.-4C>T variant is located in the Kozak consensus sequence, and although typically the -4 position is a cytosine it is known to be variable. One study showed this variant resulted in weak CHEK2 immunoreactivity in an ovarian tumour sample (Williams 2006). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000589024	SCV001739885	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000589024	SCV001957250	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004542826	SCV004774878	likely benign	CHEK2-related disorder	2019-07-09	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).