ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.134+5G>A (rs80358038)

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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 RCV001010944 SCV001171209 likely pathogenic Hereditary cancer-predisposing syndrome 2020-09-09 criteria provided, single submitter clinical testing The c.134+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 2 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). One functional study found all substitutions at this nucleotide position are deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). In addition, a variant at the same nucleotide position, BRCA1 c.134+5G>T, causes skipping of of coding exon 2 (also called exon 3 in the literature: Baert A et al. Hum. Mutat., 2018 04;39:515-526). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001221249 SCV001393280 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-07-05 criteria provided, single submitter clinical testing This sequence change falls in intron 3 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 reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 91548). 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: 30209399). This variant disrupts the c.134+5G nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 29280214, 30209399). This suggests that this nucleotide is clinically-significant, and that variants that disrupt this position are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077065 SCV000108862 likely pathogenic Breast-ovarian cancer, familial 1 2009-07-17 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077065 SCV000144420 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000077065 SCV001242403 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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