13-32330917-A-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.682-2A>G variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_000059.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.682-2A>G | splice_acceptor_variant, intron_variant | Intron 8 of 26 | 5 | NM_000059.4 | ENSP00000369497.3 | |||
BRCA2 | ENST00000530893.7 | c.313-2A>G | splice_acceptor_variant, intron_variant | Intron 8 of 26 | 1 | ENSP00000499438.2 | ||||
BRCA2 | ENST00000614259.2 | n.682-2A>G | splice_acceptor_variant, intron_variant | Intron 7 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 1430748Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0AN XY: 713654
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:2
Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.682_793del transcript (encoding predicted non-functional protein). -
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Hereditary cancer-predisposing syndrome Pathogenic:2
The c.682-2A>G pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 8 in the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration segregated with disease in one family and was observed via RT-PCR to cause aberrant splicing resulting in coding exon 8 skipping (de Garibay GR et al. Hum. Mutat., 2014 Jan;35:53-7). This alteration was also detected in 1/312 males with breast cancer who also had a positive family history of breast and/or ovarian cancer. (de Juan I et al. Fam Cancer, 2015 Dec;14:505-13). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. As such, this alteration is interpreted as a disease-causing mutation. -
This variant causes an A to G nucleotide substitution at the -2 position of intron 8 of the BRCA2 gene. RT-PCR analysis from carrier blood RNA showed that the variant allele produced only predicted non-functional transcripts (PMID: 24123850). This variant has been reported in a hereditary breast cancer (PMID: 26026974) and a hereditary breast and ovarian cancer family (PMID: 24123850). In the latter family, this variant segregated in two out of three breast cancer affected members who were tested (PMID: 24123850). 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 Pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
This sequence change affects an acceptor splice site in intron 8 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with female breast cancer, lymphoma, and/or male breast cancer (PMID: 24123850, 26026974, 29446198). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 236264). Studies have shown that disruption of this splice site results in skipping of exon 9 and/or activation of cryptic splice sites and introduces a premature termination codon (PMID: 24123850). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at