rs81002797
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.475+1G>A variant causes a splice donor 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 Pathogenic (★★★).
Frequency
Genomes: not found (cov: 33)
Consequence
BRCA2
NM_000059.4 splice_donor
NM_000059.4 splice_donor
Scores
4
2
1
Splicing: ADA: 0.9999
2
Clinical Significance
Conservation
PhyloP100: 4.85
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-32326151-G-A is Pathogenic according to our data. Variant chr13-32326151-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 51708.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32326151-G-A is described in Lovd as [Pathogenic]. Variant chr13-32326151-G-A is described in Lovd as [Likely_pathogenic]. Variant chr13-32326151-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.475+1G>A | splice_donor_variant | ENST00000380152.8 | NP_000050.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.475+1G>A | splice_donor_variant | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ExAC
AF:
AC:
1
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:10
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 03, 2016 | Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.426_475del transcript (encoding predicted non-functional protein). - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Oct 24, 2023 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 16, 2023 | This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site results in exon 5 skipping and introduces a premature termination codon (PMID: 23451180). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 51708). Disruption of this splice site has been observed in individual(s) with Fanconi Anemia and a personal and/or family history of breast and ovarian cancer (PMID: 28102861, 29176636, 29446198, 30792206). This sequence change affects a donor splice site in intron 5 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 17, 2019 | Variant summary: BRCA2 c.475+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict that the variant abolishes a 5 prime splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Colombo_2012). The variant was absent in 251000 control chromosomes (gnomAD). c.475+1G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Colombo_2012, Nakamura_2013, Arai_2018, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. The variant has also been detected along with a second BRCA2 mutation in trans in individuals affected with Fanconi anemia (e.g. Mori_2019). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (evaluation after 2014) and cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 25, 2019 | The c.475+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 4 of the BRCA2 gene. This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 May;39:593-620). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site. Further, experimental observation of the effect of this alteration, designated as IVS5+1G>A, on mRNA splicing found it lead to skipping of exon 5, leading to protein truncation (Colombo M et al. PLoS ONE, 2013 Feb;8:e57173). In addition to the clinical data presented in the literature, 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 classified as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at