chr13-32379913-G-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_000059.4(BRCA2):c.9117G>T(p.Pro3039=) variant causes a splice region, synonymous change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P3039P) has been classified as Pathogenic.
Frequency
Consequence
NM_000059.4 splice_region, synonymous
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.9117G>T | p.Pro3039= | splice_region_variant, synonymous_variant | 23/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.9117G>T | p.Pro3039= | splice_region_variant, synonymous_variant | 23/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 08, 2023 | 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 disrupts the c.9117 nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10638982, 17011978, 22632462, 23451180). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 23 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 267715). This variant has been observed in individual(s) with breast cancer, ovarian cancer, or melanoma (PMID: 29446198, 29470806, 33077847). This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 3039 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 27, 2021 | Variant summary: BRCA2 c.9117G>T (p.Pro3039Pro) alters a conserved nucleotide located at the last nucleotide of exon 23 adjacent to a canonical 5' splice donor site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 248378 control chromosomes. c.9117G>T has been reported in the literature in at-least two individuals affected with familial breast cancer (example, Rebbeck_2018, Singh_2018). Of note, a different nucleotide change, c.9117G>A, resulting in the same synonymous alteration (p.Pro3039Pro) has been widely reported among individuals/families with breast cancer worldwide (example, Rebbeck_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory and one consortium (CIMBA, cited in Rebbeck_2018 captured above) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic (CIMBA) and uncertain significance respectively. At-least one submitter cites overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at