rs397507389
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.7618-1G>A variant causes a splice acceptor change involving the alteration of a conserved nucleotide. 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: 32)
Consequence
BRCA2
NM_000059.4 splice_acceptor
NM_000059.4 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.31
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 13-32357741-G-A is Pathogenic according to our data. Variant chr13-32357741-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38110.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357741-G-A is described in Lovd as [Pathogenic]. Variant chr13-32357741-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.7618-1G>A | splice_acceptor_variant | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.7618-1G>A | splice_acceptor_variant | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Dec 09, 2010 | - - |
| 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, 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 15 of the BRCA2 gene. RNA studies have detected out-of-frame splicing in the RNA from carriers of this variant, resulting in premature truncation (PMID: 21394826, 22006311, 31843900). This variant has been detected in at least 4 individuals affected with breast, pancreatic and peritoneal cancer (PMID: 12097290, 22006311, 26681312, 35451682) and has been identified in 11 families among the CIMBA participants (PMID: 29446198). 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 | Counsyl | Jun 17, 2015 | - - |
| 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 - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 17, 2021 | This variant disrupts a canonical splice-acceptor site and interferes with normal BRCA2 mRNA splicing. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 21394826 (2011), 22006311 (2011), 29881398 (2018)) and peritoneal cancer (PMID: 22006311 (2011)). Functional studies of this variant show abnormal splicing that results in a disrupted protein product (PMIDs: 21394826 (2011) and 29881398 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 24, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 19, 2022 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: causes aberrant splicing resulting in multiple transcripts, including partial deletion of exon 16 and exon 17, predicted to result in a null allele (Whiley 2011, Fraile-Bethencourt 2018); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Murphy 2002, Walsh 2011, Tung 2016); Not observed at significant frequency in large population cohorts (gnomAD); 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; Also known as 7846-1G>A; This variant is associated with the following publications: (PMID: 12097290, 20104584, 30832263, 21990134, 21394826, 22006311, 17924331, 25085752, 26976419, 26681312, 29881398, 24240112, 23725378, 29446198, 28492532, 31843900, 31447099, 32398771, 30787465) - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 22, 2023 | This variant causes a G to A nucleotide substitution at the -1 position of intron 15 of the BRCA2 gene. RNA studies have detected out-of-frame splicing in the RNA from carriers of this variant, resulting in premature truncation (PMID: 21394826, 22006311, 31843900). This variant has been detected in at least 4 individuals affected with breast, pancreatic and peritoneal cancer (PMID: 12097290, 22006311, 26681312, 35451682) and has been identified in 11 families among the CIMBA participants (PMID: 29446198). 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 | curation | Sema4, Sema4 | Sep 23, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 21, 2022 | The c.7618-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide before coding exon 15 in the BRCA2 gene. This alteration has been reported in multiple individuals with hereditary breast and/or ovarian cancer (Whiley PJ et al. Hum. Mutat. 2011 Jun;32:678-87; Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7). RNA and minigene assays have shown that this alteration results in a majority of transcript lacking 45bp from coding exon 14 (Ambry internal data; Whiley PJ et al. Hum. Mutat. 2011 Jun;32:678-87; Fraile-Bethencourt et al. Front Genet 2018 May;9:188). Of note, this alteration is also designated as IVS15-1G>A in published literature. 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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 10, 2016 | Variant summary: The BRCA2 c.7618-1G>A variant involves the alteration of a conserved intronic nucleotide with 5/5 splice prediction tools predicting a significant impact on splicing, which is functionally supported. The variant of interest has not been observed in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change affects an acceptor splice site in intron 15 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. 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 peritoneal carcinoma (PMID: 21394826, 22006311, 26681312). This variant is also known as c.7846-1G>A and IVS15-1G>A. ClinVar contains an entry for this variant (Variation ID: 38110). 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, 21394826, 21990134). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 21394826, 22006311; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Hereditary breast ovarian cancer syndrome;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1
| Pathogenic, no assertion criteria provided | research | King Laboratory, University of Washington | Sep 01, 2019 | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 10, 2024 | - - |
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
Pathogenic
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_AG_spliceai
Position offset: 45
DS_AL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at