ClinVar Genomic variation as it relates to human health

Not observed in large population cohorts (Lek et al., 2016); In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25525159, 24156927, 9971877, 22984553, 28905878)

Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 9971877, 28905878, 30883759). ClinVar contains an entry for this variant (Variation ID: 51710). This variant has been observed in individual(s) with BRCA2-related conditions (PMID: 9971877, 24156927). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 5 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 9971877, 28905878, 30883759). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 28905878; 30883759 and 9971877). 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.

This variant causes an A to G nucleotide substitution at the +3 position of intron 5 in the BRCA2 gene. Analysis of carrier RNA found the skipping of exon 5 that is predicted to create a premature translation termination and is expected to produce an absent or non-functional protein product (PMID: 9971877, 28905878). This variant has been observed in at least three individuals affected with breast cancer (Color Internal database and an external clinical laboratory) and an individual affected with breast and/or ovarian cancer (PMID: 28905878, Universal Mutation Database). This variant also has been reported in a family affected with three cases of breast cancer and one member with breast and ovarian cancer (PMID: 9971877, 24156927). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

The c.475+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 4 in the BRCA2 gene. This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 May;39:593-620), and was also reported in another cohort of individuals with a personal or family history of breast and/or ovarian cancer (Tea MK et al. Maturitas, 2014 Jan;77:68-72). 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. One study reported that this alteration was associated with abnormal splicing (skipping of exon 5, Davy G et al. Eur J Hum Genet, 2017 Oct;25:1147-1154). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.