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

dbSNP: rs80358038

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001010944	SCV001171209	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-11	criteria provided, single submitter	clinical testing	The c.134+5G>A intronic pathogenic mutation 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. In silico splice site analysis predicts that this alteration will weaken 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 non-functional 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001221249	SCV001393280	likely pathogenic	Hereditary breast ovarian cancer syndrome	2025-01-07	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. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with pancreatic ductal adenocarcinoma (PMID: 10923033, 30274973). ClinVar contains an entry for this variant (Variation ID: 91548). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects BRCA1 function (PMID: 30209399). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477477	SCV004222558	likely pathogenic	not provided	2023-04-06	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual affected with pancreatic cancer (PMID: 30274973 (2018)). Analysis of the 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 . The variant is predicted to interfere with normal BRCA1 mRNA splicing (personal communication Ambry Genetics (http://www.ambrygen.com/)), and a functional study described the variant as causing loss of function due to the lack of cell survival (PMID: 30209399 (2018)). In addition, a related G>T variant at this same position in the intron was shown to affect splicing (PMID: 29280214 (2018), 36446827 (2023)). Based on the available information, the c.134+5G>A variant is classified as likely pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077065	SCV000108862	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2009-07-17	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077065	SCV000144420	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000077065	SCV001242403	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro