Submissions for variant NM_007294.4(BRCA1):c.5152+6T>G

dbSNP: rs80358074

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001211670	SCV000699209	pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5152+6T>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing demonstrating skipping of exon 17 (r.5075_5152del) that is predicted to result in the deletion of amino acids at positions 1692 through 1718 and the insertion of a glycine residue (p.D1692_W1718delinsG) (Landrith_2020). Numerous other pathogenic variants have been identified in exon 17 supporting a critical relevance of this domain to BRCA1 protein function. The variant was absent in 251212 control chromosomes. c.5152+6T>G has been reported in the literature in at-least one individual of Ashkenazi Jewish descent diagnosed with Breast Cancer at the age of 49 years (example, Landrith_2020 and inconclusive case counts in Judkins_2005, Shattuck-Eidens_1997). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in loss of homology directed repair (HDR) activity supporting a non-functional protein product (Findlay_2018). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. The following publications have been ascertained in the context of this evaluation (PMID: 16267036, 21523855, 9333265, 32133419, 30209399). ClinVar contains an entry for this variant (Variation ID: 125778). Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics	RCV001023624	SCV001185531	pathogenic	Hereditary cancer-predisposing syndrome	2024-05-29	criteria provided, single submitter	clinical testing	The c.5152+6T>G intronic pathogenic mutation results from a T to G substitution 6 nucleotides after coding exon 16 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on the majority of available evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001211670	SCV001383220	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-10-14	criteria provided, single submitter	clinical testing	This sequence change falls in intron 17 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer (PMID: 9333265, 36008414). This variant is also known as IVS18+6T>G. ClinVar contains an entry for this variant (Variation ID: 125778). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 17, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 32133419). This variant disrupts the c.5152+6T nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 32123317, 32761968; external communication, internal data). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998229	SCV005626136	likely pathogenic	not provided	2023-11-07	criteria provided, single submitter	clinical testing	The BRCA1 c.5152+6T>G variant has been reported in the published literature in individuals and families with a history of breast and/or ovarian cancer (PMID: 9333265 (1997)). Experimental evidence suggests this variant is damaging to BRCA1 function (PMIDs: 32133419 (2020), 30209399 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper BRCA1 mRNA splicing. Based on the available information, this variant is classified as likely pathogenic.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112524	SCV000145346	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112524	SCV001243639	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro