ClinVar Miner

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

gnomAD frequency: 0.00034  dbSNP: rs142692907
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Total submissions: 10
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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 This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae RCV001080248 SCV000253478 benign Familial cancer of breast 2021-12-17 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health 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 2020-04-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
GeneDx RCV000759041 SCV001939450 benign not provided 2015-03-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 32906215)
Genetic Services Laboratory,University of Chicago RCV000780178 SCV002066418 likely benign not specified 2022-01-03 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV002225475 SCV002505156 likely benign Hereditary breast ovarian cancer syndrome 2022-04-19 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000163080 SCV002537027 likely benign Hereditary cancer-predisposing syndrome 2021-03-19 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358565 SCV001554341 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 p.Ala392Ala variant was not identified in the literature nor was it identified in the Cosmic, MutDB, Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs142692907) as “With Likely benign allele” and ClinVar (3x as benign by Invitae, likely benign by Ambry Genetics and Color) databases. The variant was identified in control databases in 32 of 276892 chromosomes at a frequency of 0.00012 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 25 of 24032 chromosomes (freq: 0.001), Latino in 4 of 34406 chromosomes (freq: 0.00012), European Non-Finnish in 1 of 126400 chromosomes (freq: 0.000008), European Finnish in 1 of 25794 chromosomes (freq: 0.000039), and South Asian in 1 of 30782 chromosomes (freq: 0.000032); while the variant was not observed in the Other, Ashkenazi Jewish or East Asian populations. The p.Ala392Ala variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.

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