rs81002846
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000059.4(BRCA2):c.793+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000125 in 1,599,576 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 splice_donor
NM_000059.4 splice_donor
Scores
1
5
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 2.81
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 22 ACMG points.
PVS1
?
Splicing 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;
PP3
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Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 13-32331031-G-A is Pathogenic according to our data. Variant chr13-32331031-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 52437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32331031-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.793+1G>A | splice_donor_variant | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.793+1G>A | splice_donor_variant | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152090Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.91e-7 AC: 1AN: 1447486Hom.: 0 Cov.: 27 AF XY: 0.00000139 AC XY: 1AN XY: 721030
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | This variant causes a G to A nucleotide substitution at the +1 position of intron 9 of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. A variant at the same position, 793+1G>T, has been reported in RNA studies to result in exon 9 skipping and a premature translation stop signal (PMID: 30883759). This variant has been reported in four individuals affected with breast and/or ovarian cancer (PMID: 31125106, 35264596, 36980780, 3723905) and in four families among the CIMBA participants (PMID: 29446198). This variant has been reported in a multifactorial analysis with segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.862, 1.07, 1.050 and 0.920, respectively (PMID: 31131967). This variant has been identified in 1/31208 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jun 06, 2023 | affects a donor splice site in intron 9 of the BRCA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 52437) with 8 submissions describing this variant as either pathogenic or likely pathogenic. In summary, donor and acceptor splice site variants are typically truncating (PMID: 16199547), and truncating variants in BRCA2 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as pathogenic. - |
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 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 09, 2023 | This variant causes a G to A nucleotide substitution at the +1 position of intron 9 of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. A variant at the same position, 793+1G>T, has been reported in RNA studies to result in exon 9 skipping and a premature translation stop signal (PMID: 30883759). This variant has been reported in four individuals affected with breast and/or ovarian cancer (PMID: 31125106, 35264596, 36980780, 3723905) and in four families among the CIMBA participants (PMID: 29446198). This variant has been reported in a multifactorial analysis with segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.862, 1.07, 1.050 and 0.920, respectively (PMID: 31131967). This variant has been identified in 1/31208 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 18, 2020 | The c.793+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 8 of the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been reported in multiple individuals from breast, ovarian, and pancreatic cancer cohorts (Lowery M et al. J. Natl. Cancer Inst. 2018 10;110(10):1067-1074; Rebbeck T et al. Hum. Mutat. 2018 05;39(5):593-620; Teixeira N et al. Eur. J. Hum. Genet. 2018 06;26(6):848-857; Tsaousis G et al. BMC Cancer 2019 Jun;19(1)). RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition, a close match alteration, BRCA2 c.793+1G>T results in skipping of coding exon 8 (also called Exon 9) by minigene analysis (Fraile-Bethencourt E et al. J. Pathol., 2019 08;248:409-420). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 13, 2023 | This sequence change affects a donor splice site in intron 9 of the BRCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs81002846, gnomAD 0.01%). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer and with pancreatic cancer (PMID: 23961350, 29093764, 29446198, 29483665, 29506128). ClinVar contains an entry for this variant (Variation ID: 52437). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 30883759). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This mutation, which occurs in the first base of intron 9 of the BRCA2 gene, results in incorrect splicing of the mRNA produced by this allele and alteration of the reading frame. This mutation has been described in international bibliography (http://research.nhgri.nih.gov/), as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 25, 2022 | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 24, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
D;D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at