rs81002813
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong
The NM_000059.4(BRCA2):c.8754+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,650 control chromosomes in the GnomAD database, with no homozygous occurrence. 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
Consequence
NM_000059.4 splice_donor_5th_base, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.8754+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8754+5G>A | splice_donor_5th_base_variant, intron_variant | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461650Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727102
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Jul 28, 2017 | - - |
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) | May 01, 2012 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Dec 23, 2003 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not provided Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 22, 2022 | This variant causes a G to A nucleotide substitution at the +5 position of intron 21 of the BRCA2 gene. RNA studies have reported that this variant causes the out-of-frame splicing of intron 21 in RNA from carrier-derived cells, in minigene splicing assay and in mouse embryonic stem cells (PMID: 18693280, 25146914, 25382762). Moreover, this variant failed to complement Brca2-deficient mouse embryonic stem cell (PMID: 25146914). This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 18693280). 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 | Apr 28, 2022 | The c.8754+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 20 in the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. This alteration has been reported in a patient diagnosed with early-onset breast cancer who had a family history of breast cancer (Vreeswijk MP et al. Hum Mutat. 2009 Jan;30(1):107-14). Multiple splicing assays have shown this alteration results in an aberrant transcript which retains 46 nucleotides from intron 20 and would cause a translational frameshift with a predicted alternate stop codon (Vreeswijk MP et al. Hum Mutat. 2009 Jan;30(1):107-14; Hendriks G et al. Hum Mutat. 2014 Nov;35(11):1382-91; Acedo A et al. Hum Mutat. 2015 Feb;36(2):210-21). In addition, Hendriks et al. (2014) used a functional complementation assay in mouse-embryonic stem (mES) cells which showed that the alteration could not complement the lethality of mBrca2-deficient mES cells. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 31, 2021 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with retention of 46 nucleotides from intron 21, which introduces a premature termination codon (PMID: 18693280, 25146914). The resulting mRNA is expected to undergo nonsense-mediated decay. Studies have shown that this variant alters BRCA2 gene expression (PMID: 25146914). This variant has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer (HBOC) syndrome (PMID: 18693280). This variant is also known as IVS21+5G>A. ClinVar contains an entry for this variant (Variation ID: 38182). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 21 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at