rs397508045
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.92G>A(p.Trp31*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000205 in 1,460,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Consequence
NM_000059.4 stop_gained
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.92G>A | p.Trp31* | stop_gained | Exon 3 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893 | c.-278G>A | 5_prime_UTR_variant | Exon 3 of 27 | 1 | ENSP00000499438.2 | ||||
BRCA2 | ENST00000614259.2 | n.92G>A | non_coding_transcript_exon_variant | Exon 2 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250830Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135776
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460040Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3AN XY: 726428
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3
Variant allele predicted to encode a truncated non-functional protein. -
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Hereditary cancer-predisposing syndrome Pathogenic:2
This variant changes 1 nucleotide in exon 3 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in two individuals affected with breast cancer (PMID: 26911350 and doi: 10.5812/ijcm.60392) and another affected with ovarian cancer (PMID: 22776961). This variant has been identified in 1/250830 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -
The p.W31* pathogenic mutation (also known as c.92G>A), located in coding exon 2 of the BRCA2 gene, results from a G to A substitution at nucleotide position 92. This changes the amino acid from a tryptophan to a stop codon within coding exon 2. This mutation has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Schrader KA et al. Obstet Gynecol, 2012 Aug;120:235-40; Mannan AU et al. J. Hum. Genet., 2016 Jun;61:515-22; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620; Rashid MU et al, 2019 Sep;17:27). RNA studies have demonstrated that alteration results in partial skipping of coding exon 2 (exon 3 in the literature), which splices out this alteration and premature stop codon (Ambry internal data; Fraile-Bethencourt E et al J Pathol 2019 08;248(4):409-420; Tubeuf H et al. Cancer Res 2020 Sep;80(17):3593-3605); however skipping of coding exon 2 is expected to be deleterious (Caputo SM et al. Oncotarget 2018 Apr;9(25):17334-17348). Of note, this alteration is also designated as c.320G>A in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
This sequence change creates a premature translational stop signal (p.Trp31*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs397508045, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22776961, 26911350). This variant is also known as c.320G>A. ClinVar contains an entry for this variant (Variation ID: 52808). For these reasons, this variant has been classified as Pathogenic. -
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Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1
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not provided Pathogenic:1
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Familial cancer of breast Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at