ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4185+10G>C

gnomAD frequency: 0.00003  dbSNP: rs80358104
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000112277 SCV001161591 benign Breast-ovarian cancer, familial, susceptibility to, 1 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000129
Counsyl RCV000112277 SCV000488141 benign Breast-ovarian cancer, familial, susceptibility to, 1 2016-02-19 criteria provided, single submitter clinical testing
GeneDx RCV000420424 SCV000512307 likely benign not specified 2017-02-14 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp RCV001080964 SCV000560262 benign Hereditary breast ovarian cancer syndrome 2023-12-16 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000581943 SCV000688472 likely benign Hereditary cancer-predisposing syndrome 2015-02-17 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV000679695 SCV000806946 likely benign not provided 2017-07-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000420424 SCV000916706 likely benign not specified 2023-10-16 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4185+10G>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing and TrAP (Transcript-inferred Pathogenicity score) predicts the variant to be neutral. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.9e-05 in 237410 control chromosomes, predominantly at a frequency of 6.7e-05 within the African or African-American subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4185+10G>C has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Judkins_2005, Spearman_2008). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Publications reporting multifactorial probability based models predict the variant to be neutral (Lindor_2012, Easton_2007). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17924331, 16267036, 21990134, 18824701). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000420424 SCV001158540 likely benign not specified 2019-06-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000581943 SCV002629464 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112277 SCV000145009 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-02-20 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112277 SCV000297607 benign Breast-ovarian cancer, familial, susceptibility to, 1 2008-11-13 no assertion criteria provided clinical testing

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