ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.-6G>A (rs376995740)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590166 SCV000149888 uncertain significance not provided 2018-06-28 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.-6G>A, and describes a nucleotide substitution 6 base pairs upstream of the ATG translational start site in the 5' untranslated region (UTR). The surrounding sequence, with the base that is substituted in brackets, is TGAG[G/A]TCGT. This variant has been reported in individuals with acute myeloid leukemia, breast cancer, or MMR-proficient colon cancer (Tung 2015, Hirsch 2016, Pearlman 2017). CHEK2 c.-6G>A lies within the ?consensus? Kozak sequence, the nucleotides which play a major role in the initiation of translation and which lie just upstream of the ATG start codon. This variant was observed at an allele frequency of 0.22% (53/23,662) in individuals of African ancestry in large population cohorts (Lek 2016). The guanine (G) nucleotide that is altered is not conserved. While the c.-6G>A variant does not alter or create a new start codon (ATG), it is possible that it may have an effect on the initiation of the translation process and impact protein levels. Based on the currently available information, it is unclear whether CHEK2 c.-6G>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000197200 SCV000488950 uncertain significance Familial cancer of breast 2016-08-03 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000722128 SCV000698814 likely benign not specified 2018-08-27 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.-6G>A variant involves the alteration of a conserved nucleotide, which is the first nucleotide of exon 2 and located in 5'UTR. One in silico tool predicts the variant being a polymorphism. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0002 in 269654 control chromosomes, predominantly within the African subpopulation at a frequency of 0.0022 in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (HBOC) phenotype (0.0022 vs. 0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African 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 reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as Uncertain significance (2x) or Likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.
Color RCV000776065 SCV000910728 likely benign Hereditary cancer-predisposing syndrome 2015-02-16 criteria provided, single submitter clinical testing

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