13-32370558-G-A
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.8487+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,402 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 splice_donor, intron
NM_000059.4 splice_donor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.92
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 12 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.015111631 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-32370558-G-A is Pathogenic according to our data. Variant chr13-32370558-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 52602.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32370558-G-A is described in Lovd as [Pathogenic]. Variant chr13-32370558-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.8487+1G>A | splice_donor_variant, intron_variant | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.8487+1G>A | splice_donor_variant, intron_variant | 5 | NM_000059.4 | ENSP00000369497.3 | ||||
| BRCA2 | ENST00000530893.7 | c.8118+1G>A | splice_donor_variant, intron_variant | 1 | ENSP00000499438.2 | |||||
| BRCA2 | ENST00000614259.2 | n.*545+1G>A | splice_donor_variant, intron_variant | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457402Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 725408
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GnomAD4 genome
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32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:17Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
| 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 | Sharing Clinical Reports Project (SCRP) | Nov 30, 2012 | - - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Aug 10, 2015 | IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 - |
| Pathogenic, no assertion criteria provided | case-control | Molecular Oncology, Hospital Universitario Central de Asturias (HUCA) | May 24, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 30, 2018 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 03, 2023 | This sequence change affects a donor splice site in intron 19 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 12606139, 16619214, 17591842, 24156927). This variant is also known as IVS19+1G>A. ClinVar contains an entry for this variant (Variation ID: 52602). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134, 25085752). Studies have shown that disruption of this splice site results in skipping of exon 19, but is expected to preserve the integrity of the reading-frame (PMID: 12606139, 16619214, 22632462; Invitae). This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Gly2793Arg) have been determined to be pathogenic (PMID: 12442275, 15889636, 16030099, 23108138, 23233716, 25085752, 25777348). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 05, 2018 | Variant summary: BRCA2 c.8487+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 the variant abolishes a 5' splicing donor site. At least two publications report experimental evidence supporting these predictions, which causes skipping of exon 19 leading to an abnormal protein product (p.Ille2778_Gln2829del)(Chen_2006, Agata_2003). The variant was absent in 276832 control chromosomes. c.8487+1G>A has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer, indicating the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 08, 2016 | The c.8487+1G>A variant in BRCA2 has been reported in at least 9 individuals wit h BRCA2-associated cancers (Chen 2006, Veschi 2007,Breast Cancer Information Cor e (BIC) database), and was absent from large population studies. This variant oc curs in the invariant region (+/- 1,2) of the splice consensus sequence and is p redicted to cause altered splicing leading to an abnormal or absent protein. In vitro functional studies provide evidence that the c.8487+1G>A variant impacts s plicing (Agata 2003, Acedo 2012, Chen 2006). Heterozygous loss of BRCA2 function is an established disease mechanism in hereditary breast and ovarian cancer (HB OC). Furthermore, this variant was classified as Pathogenic on August 10, 2015 b y the ClinGen-approved ENIGMA expert panel (ClinVar SCV000244485.1). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an a utosomal dominant manner based upon absence from controls, functional evidence, and predicted impact to the protein. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 12, 2021 | This variant is located in a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. The variant has been described in individuals with breast cancer in the published literature (PMID: 30702160 (2019), 29446198 (2018), 28294317 (2017), 27062684 (2016), 26681312 (2015), 24156927 (2014)). In addition, this variant has been shown to result in BRCA2 exon 19 skipping and the deletion of 52 amino acids from the BRCA2 protein ((PMID: 32398771 (2020), 22632462 (2012), 16619214 (2006)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 08, 2022 | Canonical splice site variant demonstrated to result in an in-frame deletion of the critical DSS1 contacting residues of the DNA binding domain (Yang 2002, Agata 2003, Chen 2006, Acedo 2012); Observed in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Agata 2003, Chen 2006, Veschi 2007, Tea 2014, Lang 2017); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (gnomAD); Also known as 8715+1G>A; This variant is associated with the following publications: (PMID: 17591842, 26681312, 24728327, 21990134, 12606139, 22632462, 17924331, 16619214, 27060066, 24156927, 25085752, 29446198, 29061375, 31209999, 25525159, 32398771, 30787465, 31825140, 30702160, 28294317, 12228710) - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 27, 2021 | The BRCA2 c.8487+1G>A variant (rs81002798), also known as IVS19+1, is reported in the literature in several individuals and families affected with breast and/or ovarian cancer (Agata 2003, Chen 2006, Gao 2020, Veschi 2007). This variant is also reported in ClinVar (Variation ID: 52602), and is classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 19, and functional assays demonstrate skipping of exon 19 (Agata 2003, Chen 2006). Based on available information, this variant is considered to be pathogenic. References: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/ Agata S et al. The BRCA2 sequence variant IVS19+1G-->A leads to an aberrant transcript lacking exon 19. Cancer Genet Cytogenet. 2003 Mar;141(2):175-6. PMID: 12606139. Chen X et al. Intronic alterations in BRCA1 and BRCA2: effect on mRNA splicing fidelity and expression. Hum Mutat. 2006 May;27(5):427-35. PMID: 16619214. Gao X et al. Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients. Hum Mutat. 2020 Mar;41(3):696-708. PMID: 31825140. Veschi S et al. High prevalence of BRCA1 deletions in BRCAPRO-positive patients with high carrier probability. Ann Oncol. 2007 Jun;18 Suppl 6:vi86-92. PMID: 17591842. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 22, 2021 | This variant causes a G to A nucleotide substitution at the +1 position of intron 19 of the BRCA2 gene. It is also known as IVS19+1G>A in the literature. Functional RNA studies have shown that this variant results in the skipping of exon 19, causing an in-frame deletion of 52 amino acids within the essential DNA binding domain of BRCA2 protein (PMID: 12606139, 16619214, 22632462). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 16619214, 24156927, 28423363; Color internal data). Multifactorial likelihood analyses based on genetic data using personal/family history, co-segregation, and co-occurrence predict that this variant has a high probability of being deleterious (PMID: 17924331, 21990134, 25085752). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 26, 2024 | The c.8487+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 18 of the BRCA2 gene. This mutation has been reported in multiple individuals with personal and/or family histories consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Agata S et al. Cancer Genet. Cytogenet. 2003 Mar;141:175-6; Chen X et al. Hum. Mutat. 2006 May;27:427-35; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). Multiple splicing assays have shown that this alteration leads to complete skipping of coding exon 18, resulting in a predicted in-frame deletion of 52 amino acid residues in a functionally important region of the BRCA2 protein (Ambry internal data; Mesman RLS et al. Genet Med 2020 08;22(8):1355-1365; Chen X et al. Hum. Mutat. 2006 May;27:427-35; Acedo A et al. Breast Cancer Res. 2012 May 25;14:R87; Agata S et al. Cancer Genet. Cytogenet. 2003 Mar;141:175-6). 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. - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 20, 2021 | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 21, 2023 | - - |
not specified Other:1
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
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