Submissions for variant NM_007194.4(CHEK2):c.-6G>A

gnomAD frequency: 0.00065  dbSNP: rs376995740

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590166	SCV000149888	uncertain significance	not provided	2024-08-15	criteria provided, single submitter	clinical testing	Nucleotide is not conserved across species and the substitution has no predicted effect on splicing; Published functional studies demonstrate no damaging effect: produced transcripts similar to wildtype in a minigene assay (PMID: 37725924); Observed in individuals with breast, colon, and other cancers (PMID: 25186627, 27534895, 27978560, 35534704); Alters the Kozak sequence, which plays a major role in the initiation of translation; This variant is associated with the following publications: (PMID: 27534895, 25186627, 27978560, 14687034, 3313277, 35534704, 37725924)
Counsyl	RCV000197200	SCV000488950	uncertain significance	Familial cancer of breast	2016-08-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000722128	SCV000698814	benign	not specified	2021-06-05	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.-6G>A is located in the untranslated mRNA region upstream of the initiation codon. Although this region is indicated to be affected by pseudogene interference, a BLAT search for the reference sequence (TTTTGAGgTCGTGATGTCTCGGGAGTCGGA, i.e. a 25 or 30 nucleotide sequence surrounding the location of the variant) gave no hits on other chromosomes/regions. The variant allele was found at a frequency of 0.00013 in 244186 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 6.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.-6G>A has been reported in the literature in an African American female patient affected with breast cancer (Tung 2014) and in an MMR-proficient colon cancer patient (race not specified) (Pearlman 2016), however the variant was also reported to be found in 4/2559 African American women, who are older than age 70 years, and who have never had cancer (in the FLOSSIES database). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=1; VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the absence of any evidence supporting an actionable outcome as outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000776065	SCV000910728	likely benign	Hereditary cancer-predisposing syndrome	2015-02-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590166	SCV001134173	likely benign	not provided	2023-04-28	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV003224152	SCV003919795	uncertain significance	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer	2022-07-07	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in 1 individual with breast cancer and 1 individual with MMR-proficient colorectal cancer (Tung 2015 PMID:25186627; Pearlman 2017 PMID:27978560). This variant is present in the Genome Aggregation Database (Highest reported MAF: 0.2% [89/41178]; https://gnomad.broadinstitute.org/variant/22-28734727-C-T?dataset=gnomad_r3), and in ClinVar, with classifications ranging benign to uncertain significance (Variation ID:128041). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant is located 6 nucleotides upstream from the initiation codon in the conserved Kozak sequence, which is critical for initiation of translation. However, it is unclear what effect this variant may have. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000722128	SCV004024672	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000197200	SCV004044107	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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357979	SCV001553595	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 c.-6G>A variant was identified in 2 of 5216 proband chromosomes (frequency: 0.0004) from individuals with breast and colon cancer and was present in 5 of 19,768 control chromosomes (frequency: 0.0003) from healthy individuals (Tung 2015, Pearlman 2017). The variant was also identified in dbSNP (rs376995740) as “with other allele”, in ClinVar (classified as "likely benign" by Color and Integrated Genetics and "uncertain significance" by GeneDx and Counsyl). The variant was identified in control databases in 53 of 269,654 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 53 of 23,662 chromosomes (freq: 0.00224), but not in the “Other”, Latino, European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant lies 6 base pairs upstream of the ATG start site and is part of the Kozak consensus sequences which is important for translation initiation, although a G is generally present at the -6 position it is known to vary at this position. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV004542827	SCV004767941	likely benign	CHEK2-related disorder	2021-05-06	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).