ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4185G>A (p.Gln1395=) (rs80356857)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567384 SCV000673016 pathogenic Hereditary cancer-predisposing syndrome 2016-02-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Last nucleotide of exon,Rarity in general population databases (dbsnp, esp, 1000 genomes),Other data supporting pathogenic classification,Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112286 SCV000145018 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112286 SCV000325880 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779909 SCV000916819 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-26 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4185G>A (p.Gln1395Gln) alters a conserved nucleotide located at the last nucleotide of an exon and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes/weakens a 5' splicing donor site. Four predict the variant abolishes/weakens a 3' acceptor site. Multiple publications report experimental evidence that this variant affects mRNA splicing (Claes_2003, Wappenschmidt_2012) and one reports reduced expression of BRCA1 protein levels (Taylor_1998). The variant was absent in 237624 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Claes_2003, Wang_2014, Palmero _2018, Wappenschmidt_2012) . These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories have classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000112286 SCV000296387 pathogenic Breast-ovarian cancer, familial 1 2015-09-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759533 SCV000888907 pathogenic not provided 2015-09-14 criteria provided, single submitter clinical testing

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