chr13-32326615-T-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.631+2T>A variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000059.4 splice_donor, 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.631+2T>A | splice_donor_variant, intron_variant | Intron 7 of 26 | 5 | NM_000059.4 | ENSP00000369497.3 | |||
BRCA2 | ENST00000530893.7 | c.262+2T>A | splice_donor_variant, intron_variant | Intron 7 of 26 | 1 | ENSP00000499438.2 | ||||
BRCA2 | ENST00000614259.2 | n.631+2T>A | splice_donor_variant, intron_variant | Intron 6 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:2
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not provided Pathogenic:1
This variant is denoted BRCA2 c.631+2T>A or IVS7+2T>A and consists of a T>A nucleotide substitution at the +2 position of intron 7 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 859+2T>A. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. While BRCA2 c.631+2T>A has not, to our knowledge, been reported in the literature, another variant at the same position, BRCA2 c.631+2T>G, has been observed in individuals with hereditary breast and/or ovarian cancer syndrome, with functional studies revealing impacts on splicing and protein expression (Pyne 2000, Biswas 2011, Wong-Brown 2015). Based on the current evidence, we consider BRCA2 c.631+2T>A to be pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at