ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4357+6T>C (rs80358143)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031166 SCV000325932 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000767300 SCV000897863 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-31 criteria provided, single submitter clinical testing Data used in classification: The variant was observed in 8 independent UK families undergoing clinical diagnostic testing, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (8/16,600 in familial cases against 0/63,369 GNOMAD NFE controls pexact= 3e-06). At least 11 additional families have been identified in the UK (source DMuDB, these are not included in the previous dataset).There are additional reports of this variant on ClinVar. In the remainder of the GNOMAD populations (75,263 individuals), the frequency of this variant is 0. mRNA analysis of 2 patient samples and 5 controls was performed in a UK diagnostic laboratory on puromycin treated short term PHA stimulated lymphocyte cultures which showed that approx. 42.5% of the total RNA product was abnormally spliced excluding the whole of BRCA1 exon 12 resulting in disruption of the reading frame with incorporation of premature STOP codon at the start of BRAC1 exon 13. Skipping of exon13 (172 bases; out of frame) is also reported in Walker et al. Human Mutation 2013 and Gayther et al 1995 Nat Genet. PMID:7493024.. Additional data (not used in classification): Of note, insilico predictions of splicing effect for this variant were not strong (% change MaxEnt Score: -5.05, % change NNS Score: -6.95). The four UK families for whom pedigree data were available had a strong pattern of HBOC (Manchester score 20, 31, 25, 33). Additional samples from affected individual were not available for segregation analyses.
Color Health, Inc RCV000775143 SCV000909268 pathogenic Hereditary cancer-predisposing syndrome 2020-03-19 criteria provided, single submitter clinical testing
Invitae RCV000767300 SCV001496382 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-09-15 criteria provided, single submitter clinical testing This sequence change falls in intron 12 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with a personal and/or family history of breast and/or ovarian cancer (PMID: 7493024, 29446198, 30586678). This variant is also known as 4476+6T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 37585). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 30586678). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000031166 SCV000053766 uncertain significance Breast-ovarian cancer, familial 1 2006-10-06 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031166 SCV000145072 uncertain significance Breast-ovarian cancer, familial 1 1999-06-22 no assertion criteria provided clinical testing

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