ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1176G>A (p.Ala392=) (rs142692907)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163080 SCV000213582 likely benign Hereditary cancer-predisposing syndrome 2014-09-25 criteria provided, single submitter clinical testing
Invitae RCV000195525 SCV000253478 benign Familial cancer of breast 2017-12-17 criteria provided, single submitter clinical testing
Color RCV000163080 SCV000684563 likely benign Hereditary cancer-predisposing syndrome 2016-05-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759041 SCV000888099 likely benign not provided 2018-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780178 SCV000917227 benign not specified 2018-12-26 criteria provided, single submitter clinical testing Variant summary: The variant, CHEK2 c.1176G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational 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 0.00014 in 301872 control chromosomes (gnomAD and Momozawa_2018), predominantly at a frequency of 0.001 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 3.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. The variant c.1176G>A has been reported in the literature in individuals affected with breast cancer (Wang_2015). However, this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (PMS2 c.2186_2187delTC, p.Leu729fsX6), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (X1) or likely benign (X1). Based on the evidence outlined above, the variant was classified as benign.

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