rs1555285132
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_ModeratePM2PP5_Strong
The NM_000059.4(BRCA2):c.6842-2A>G variant causes a splice acceptor, intron change. 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 Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
BRCA2
NM_000059.4 splice_acceptor, intron
NM_000059.4 splice_acceptor, intron
Scores
4
2
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 6.61
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 Likely_pathogenic. Variant got 8 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.009261968 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.9, offset of 43, new splice context is: ttattaaatgaatttgacAGgat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-32344556-A-G is Pathogenic according to our data. Variant chr13-32344556-A-G is described in ClinVar as [Uncertain_significance]. Clinvar id is 491309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr13-32344556-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.6842-2A>G | splice_acceptor_variant, intron_variant | 5 | NM_000059.4 | ENSP00000369497.3 | ||||
| BRCA2 | ENST00000530893.7 | c.6473-2A>G | splice_acceptor_variant, intron_variant | 1 | ENSP00000499438.2 | |||||
| BRCA2 | ENST00000614259.2 | n.6842-2A>G | splice_acceptor_variant, intron_variant | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1353336Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0AN XY: 678264
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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1353336
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24
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0
AN XY:
678264
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 10, 2020 | This variant causes an A to G nucleotide substitution at the -2 position of intron 11 of the BRCA2 gene. This variant has not been reported in individuals affected with hereditary cancer in the literature although an exon 12 deletion has been reported in a breast/ovarian cancer patient (PMID: 30555256). Several lines of evidence suggest that deletion of exon 12 is tolerated in normal tissues. Alternative splicing of exon 12 was reported in multiple control samples (PMID: 10363970, 15026808, 19795481, 32046981, 32133419). A functional study reported that a similar canonical acceptor site variant (6842-1G>A with demonstrated in exon 12 skipping) retained protein function, as assayed by repair activity and BRCA2-null cell complementation studies, and failed to segregate with breast cancer in a family (PMID: 32046981). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 28, 2021 | The c.6842-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 11 in the BRCA2 gene. 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. However, RNA studies have demonstrated that this alteration as well as close match alterations at this donor site result in an increase in a transcript predicted to lead to a protein with an in-frame deletion of coding exon 11 (also known as exon 12 in the literature; Ambry internal data; Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). This exon may be clinically dispensable based on partially retained homology directed DNA repair activity (Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). In addition, the literature describes a patient with a splice variant causing coding exon 11 skipping variant in trans with a truncating BRCA2 variant in an individual without apparent Fanconi Anemia; although the degree of exon skipping is uncertain (Li L et al. Hum. Mutat., 2009 Nov;30:1543-50; Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). Thus, the clinical impact of of this variant and its resulting protein cannot be predicted. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1
| Likely pathogenic, flagged submission | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Jan 18, 2017 | This c.6842-2A>G variant has not previously been reported in public databases, nor been observed in our patient cohort. This variant affects the invariant acceptor splice site of intron 11. While not validated for clinical use, one computer-based algorithm predicts this variant to activate a cryptic splice site within exon 12 at position c.6843_6844GA, which would result in the lost of nucleotide c.6842 to c.6844 and an inframe glycine deletion at position 2281 . It is thus interpreted as a likely pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
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)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at