13-32340587-G-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.6232G>T(p.Gly2078*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.6232G>T | p.Gly2078* | stop_gained | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.5863G>T | p.Gly1955* | stop_gained | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.6232G>T | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 45
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
PVS1, PM2_Supporting, PM5_PTC_Strong c.6232G>T, located in exon 11 of the BRCA2 gene, is a nonsense variant expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay, p.(Gly2078*) (PVS1, PM5_PTC_Strong). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). No effect is predicted on splicing by SpliceAI. To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. This variant has been reported in the ClinVar database (1x pathogenic, 1x likely pathogenic), and in BRCA Exchange database as not yet reviewed, but it has not been reported in LOVD database. Based on currently available information, the variant c.6232G>T should be considered a pathogenic variant. -
Familial cancer of breast Pathogenic:1
- -
Hereditary breast ovarian cancer syndrome Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant has not been reported in the literature in individuals with BRCA2-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gly2078*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at