Submissions for variant NM_007294.4(BRCA1):c.4675+3A>G

dbSNP: rs80358082

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164653	SCV000215318	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-22	criteria provided, single submitter	clinical testing	The c.4675+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 13 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. Using two different splice site prediction tools, this alteration is predicted by BDGP to abolish the native splice donor site, but is predicted to weaken (but not abolish) the efficiency of the native splice donor site by ESEfinder; however direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000463988	SCV000549316	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-05-06	criteria provided, single submitter	clinical testing	This sequence change falls in intron 14 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 disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 32438681). ClinVar contains an entry for this variant (Variation ID: 185264). 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 activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000463988	SCV000918708	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-12-16	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4675+3A>G alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Internal RNA analysis have provided experimental evidence that this variant affects mRNA splicing by activation of a cryptic splice site resulting in partial exon 14 deletion and the introduction of a premature termination codon [r.4665_4675del (p.Gln1556Glyfs*14)]. The variant was absent in 251032 control chromosomes. c.4675+3A>G has been reported in the literature in at-least oneindividual affected with Breast and/or Ovarian Cancer (example, Santonocito_2020) . The following publication has been ascertained in the context of this evaluation (PMID: 32438681). ClinVar contains an entry for this variant (Variation ID: 185264). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985423	SCV001133594	uncertain significance	not provided	2021-07-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000985423	SCV004234650	uncertain significance	not provided	2023-03-20	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353748	SCV000591533	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 c.4675+3A>G variant was not identified in the literature nor was it identified in the LOVD 3.0 and UMD-LSDB database. The variant was identified in dbSNP (rs80358082) as “with pathogenic, uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, and Integrated Genetics). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). In other laboratories, a likely pathogenic variant was observed at the same loci with a different nucleotide change (c.4675+3A>T). The c.4675+3A>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 2 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicted a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.