Submissions for variant NM_007294.4(BRCA1):c.134+1G>C

dbSNP: rs80358043

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	RCV000589448	SCV000698848	likely pathogenic	Hereditary breast ovarian cancer syndrome	2016-11-14	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.134+1G>C variant involves the alteration of a conserved intronic nucleotide at a position known to affect splicing with 5/5 splice prediction tools predict the loss of a splicing site and ESE finder predicts alterations to ESE binding, however, these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications. However, a reputable database with a classification from 2002 cites the variant as "pathogenic." In addition, other variants located at this position, c.134+1G>A and c.134+1G>T, have been cited as "pathogenic." Therefore, the variant of interest has been classified as a "Likely Pathogenic" variant until additional information confirming the co-segregation with disease and an in-vitro/in-vivo impact on splicing are obtained.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000589448	SCV001209577	pathogenic	Hereditary breast ovarian cancer syndrome	2022-06-09	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change affects a donor splice site in intron 3 of the BRCA1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with BRCA1-related conditions (PMID: 28176296, 29446198). ClinVar contains an entry for this variant (Variation ID: 125563). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects BRCA1 function (PMID: 30209399). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800397	SCV002046865	pathogenic	not specified	2021-04-12	criteria provided, single submitter	clinical testing	This variant is located in a canonical splice-donor site and interferes with normal BRCA1 mRNA splicing. To the best of our knowledge, this variant has not been reported in individuals affected with BRCA1-related diseases in the published literature. One functional study showed this variant apparently lost functional activity in a large-scale study using a haploid cell line (PMID: 30209399 (2018)). This variant has not been reported in large, multi-ethnic general populations. Internal laboratory data indicates that this variant was detected in an individual with a phenotype consistent with disease. Based on the available information, this variant is classified as pathogenic.
Ambry Genetics	RCV004019598	SCV005025695	pathogenic	Hereditary cancer-predisposing syndrome	2024-02-05	criteria provided, single submitter	clinical testing	The c.134+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 2 of the BRCA1 gene. One functional study found that this nucleotide substitution is non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 Oct;562:217-222). 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. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111847	SCV000144413	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2002-06-20	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000111847	SCV001241928	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro