NM_000059.4:c.8487+3A>G
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.8487+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000137 in 1,457,264 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_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.8487+3A>G | splice_region_variant, intron_variant | Intron 19 of 26 | 5 | NM_000059.4 | ENSP00000369497.3 | |||
| BRCA2 | ENST00000530893.7 | c.8118+3A>G | splice_region_variant, intron_variant | Intron 19 of 26 | 1 | ENSP00000499438.2 | ||||
| BRCA2 | ENST00000614259.2 | n.*545+3A>G | splice_region_variant, intron_variant | Intron 18 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1457264Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 725356
GnomAD4 genome
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:2
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Hereditary cancer-predisposing syndrome Pathogenic:2
The c.8487+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 18 in the BRCA2 gene. This nucleotide position is well conserved in available vertebrate species. This alteration was seen in conjunction with a second BRCA2 mutation in a child diagnosed with Fanconi anemia at age 11 months (Myers K et al. Pediatr Blood Cancer. 2012 Mar;58(3):462-5). RNA analyses have found that this alteration causes aberrant splicing leading to skipping of coding exon 18 (Ambry internal data; Acedo A et al. Breast Cancer Res. 2012 May 25;14(3):R87). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. -
This variant causes an A to G nucleotide substitution at the +3 position of intron 19 splice donor site of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Multiple RNA studies have shown that this variant causes an in-frame skipping of exon 19 that encodes DNA binding domain (PMID: 22632462; ClinVar SCV000668580.3, SCV001446381.1). This variant has been reported in individuals affected with hereditary breast and/or ovarian cancer (PMID: 27376475, Color internal data). This variant has also been observed in compound heterozygous state with c.3264dupT in a child affected with Fanconi anemia with family history of ovarian and pancreatic cancers (PMID: 21548014) and in homozygosity in an unrelated child affected with Fanconi anemia (ClinVar SCV001446381.1, communication with an external laboratory). 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. -
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1Uncertain:1
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Cerebral palsy;C1384666:Hearing impairment;C4022738:Neurodevelopmental delay Pathogenic:1
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BRCA2-related disorder Pathogenic:1
The BRCA2 c.8487+3A>G variant is predicted to interfere with splicing. This variant has been reported along with a second causative variant in individuals with medulloblastoma and Fanconi anemia (DeWire et al. 2009. PubMed ID: 19530235; Chandrasekharappa et al. 2013. PubMed ID: 23613520; Internal Data, PreventionGenetics). This variant has been reported in the heterozygous state in one individual in a cohort study of prospective hereditary breast and ovarian cancer patients (Schenkel et al. 2016. PubMed ID: 27376475). This variant has not been reported in a large population database, indicating this variant is rare. RT-PCR studies suggest this variant impacts mRNA splicing and results in in-frame skipping of exon 19 (Acedo et al. 2012. PubMed ID: 22632462). This variant is interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/52603/). This variant is interpreted as pathogenic. -
not provided Pathogenic:1
This variant has been reported in an individual with Fanconi Anemia type D1 in the published literature (PMIDs: 19530235 (2009), 21548014 (2012) and 23613520 (2013)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on BRCA2 mRNA splicing yielded inconclusive predictions. A splicing functional assay, however, showed that this variant results in exon 19 skipping and a significant reduction of the canonical transcript (PMID: 22632462 (2012)). This variant has not been reported in large, multi-ethnic general populations. Therefore, we predict that this variant is likely pathogenic. -
Malignant tumor of breast Pathogenic:1
The BRCA2 c.8487+3A>G variant was identified in dbSNP (ID: rs81002806) “With uncertain significance allele”, HGMD as a “Disease causing mutation”, ClinVar database, the BIC database (1 X with unknown clinical importance), and UMD (1 X as a causal variant). The c.8487+3A>G variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 3 of 5 different programs; however, this information is not predictive enough to assume pathogenicity. Functional analysis of the variant was performed by lymphocyte RT-PCR and hybrid minigene assays in study by Acedo (2012); the result of the c.8487+3A>G variant was found to be exon 19 skipping. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as predicted pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
This sequence change falls in intron 19 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 likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with Fanconi anemia and/or hereditary breast and ovarian cancer (PMID: 21548014, 23613520, 27376475). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as IVS19+3A>G. ClinVar contains an entry for this variant (Variation ID: 52603). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 19, but is expected to preserve the integrity of the reading-frame (PMID: 22632462). 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. -
Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1 Other:1
Variant interpreted as Likely pathogenic and reported on 03-21-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at