rs886040949
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000059.4(BRCA2):c.8954-5A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. 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 Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 33)
Consequence
BRCA2
NM_000059.4 splice_region, splice_polypyrimidine_tract, intron
NM_000059.4 splice_region, splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.9985
2
Clinical Significance
Conservation
PhyloP100: 3.23
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 11 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
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 13-32379745-A-G is Pathogenic according to our data. Variant chr13-32379745-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 267712.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32379745-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.8954-5A>G | splice_region_variant, splice_polypyrimidine_tract_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.8954-5A>G | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:14
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:4
| Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 16, 2018 | Not found in the total gnomAD dataset, and the data is high quality (0/276278 chr). Found in at least one symptomatic patient. Predicted to negatively affect a known splice site. Nucleotide conservation is uninformative. Assessment of experimental evidence suggests this variant results in abnormal protein function. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 28, 2019 | Non-canonical splice site variant demonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Menendez 2012, de Garibay 2014 Santos 2014, Baert 2017); Observed in individuals with personal and family history consistent with HBOC (de Juan Jimenez 2013, Santos 2014, Peixoto 2015); Not observed in large population cohorts (Lek 2016); Also known as 9182-5A>G; This variant is associated with the following publications: (PMID: 26187060, 24916970, 23479189, 31131967, 30702160, 30415210, 21735045, 24607278, 24123850, 29280214) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2024 | This sequence change falls in intron 22 of the BRCA2 gene. It does not directly 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. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast cancer and/or hereditary breast and ovarian cancer (PMID: 21735045, 23479189, 24123850, 24607278, 24916970, 30702160). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 267712). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 21735045, 24123850, 24607278; Invitae). For these reasons, this variant has been classified as Pathogenic. - |
| Likely pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Dec 17, 2015 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 19, 2016 | Variant summary: The BRCA2 c.8954-5A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict an alteration on normal splicing, which is confirmed by functional studies which shows the variant incudes aberrant splicing of intron 22 with the retention of its last 4 bp, which is predicted to result in out of frame product (de Garibay_2014, Menendez_2012, Santos_2014). This variant is absent in 120924 control chromosomes, but was reported in numerous affected individuals in the literature, including one family in which 1 carrier unaffected, two families with one non-carrier in each family had HBOC. These families show some level of non-segregation. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:2
| 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 | BRCAlab, Lund University | Mar 02, 2020 | - - |
Familial cancer of breast Pathogenic:2
| Likely pathogenic, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 26, 2024 | Criteria applied: PVS1,PM5_STR,PM2_SUP - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Oct 10, 2022 | This variant causes an A to G nucleotide substitution at the -5 position of intron 22 of the BRCA2 gene. RNA studies found that this variant causes out-of-frame splicing of intron 22 (PMID: 21735045, 24123850, 24607278, 29280214), resulting in premature truncation. This variant has been reported in at least seven individuals affected with breast or ovarian cancer (PMID: 23479189, 24607278, 26187060, 35918668, DOI: 10.5603/OCP.2020.0026) and in families suspected of being affected with hereditary breast and ovarian cancer (PMID: 21735045, 24123850, 30415210, 33875706). 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. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 21, 2023 | The c.8954-5A>G intronic variant results from an A to G substitution 5 nucleotides upstream from coding exon 22 in the BRCA2 gene. This alteration has been identified in several hereditary breast cancer families, and was found to segregate with disease in one family (Menéndez M et al. Breast Cancer Res. Treat., 2012 Apr;132:979-92; Santos C et al. J Mol Diagn, 2014 May;16:324-34; de Juan Jiménez I et al. Fam. Cancer, 2013 Dec;12:767-77). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. RT-PCR and minigene analyses determined that this alteration results in the creation of a novel splice acceptor site that causes an out of frame retention of 4 nucleotides of intron 21 (also called intron 22 in the literature) and results in a truncated mRNA transcript (Amrby internal data; Menéndez M et al. Breast Cancer Res. Treat., 2012 Apr;132:979-92; de Garibay GR et al. Hum. Mutat., 2014 Jan;35:53-7; Santos C et al. J Mol Diagn, 2014 May;16:324-34; Baert A et al. Hum. Mutat. 2018 Apr;39(4):515-526). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 27, 2023 | _x000D_ Criteria applied: PS3_MOD, PS4_MOD, PM2_SUP, PP3 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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: 1
DS_AL_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at