13-32379740-CTCCAAACAGTTATACTGAGTATTTGGCGTCCATCATCAGATTTATATTCTCTGTTAACAGAAGGAAAGAGATACAGAATTTATCATCTTGCAACTTCAAAATCTAAAAGTAAATCTGAAAGAGCTAACATACAGTTAGCAGCGACAAAAAAAACTCAGTATCAACAACTACCGGTACAAACCTTTCATTGTAATTTTTCAGTTTTGATAAGTGCTTGTTAGTTTATGGAATCTCCATATGTTGAATTTTTGTTTTGTTTTCTGTAGGTTTCAGATGAAATTTTA-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM4PP5_Moderate
The NM_000059.4(BRCA2):c.8954-8_9136del(p.Ile2986_Phe3046del) variant causes a conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 32)
Consequence
BRCA2
NM_000059.4 conservative_inframe_deletion
NM_000059.4 conservative_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.16
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 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000059.4.
PP5
Variant 13-32379740-CTCCAAACAGTTATACTGAGTATTTGGCGTCCATCATCAGATTTATATTCTCTGTTAACAGAAGGAAAGAGATACAGAATTTATCATCTTGCAACTTCAAAATCTAAAAGTAAATCTGAAAGAGCTAACATACAGTTAGCAGCGACAAAAAAAACTCAGTATCAACAACTACCGGTACAAACCTTTCATTGTAATTTTTCAGTTTTGATAAGTGCTTGTTAGTTTATGGAATCTCCATATGTTGAATTTTTGTTTTGTTTTCTGTAGGTTTCAGATGAAATTTTA-C is Pathogenic according to our data. Variant chr13-32379740-CTCCAAACAGTTATACTGAGTATTTGGCGTCCATCATCAGATTTATATTCTCTGTTAACAGAAGGAAAGAGATACAGAATTTATCATCTTGCAACTTCAAAATCTAAAAGTAAATCTGAAAGAGCTAACATACAGTTAGCAGCGACAAAAAAAACTCAGTATCAACAACTACCGGTACAAACCTTTCATTGTAATTTTTCAGTTTTGATAAGTGCTTGTTAGTTTATGGAATCTCCATATGTTGAATTTTTGTTTTGTTTTCTGTAGGTTTCAGATGAAATTTTA-C is described in ClinVar as [Pathogenic]. Clinvar id is 429037.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8954-9_9135del | exon_loss_variant | 23/27 | 5 | NM_000059.4 | ENSP00000369497.3 | |||
BRCA2 | ENST00000530893.7 | c.8585-9_8766del | exon_loss_variant | 23/27 | 1 | ENSP00000499438.2 | ||||
BRCA2 | ENST00000380152.8 | c.8954-9_9135del | p.Ile2986fs | frameshift_variant | 23/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.8585-9_8766del | p.Ile2863fs | frameshift_variant | 23/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*1012-9_*1193del | conservative_inframe_deletion | 23/26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259.2 | n.*1012-9_*1193del | exon_loss_variant | 22/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 11, 2016 | This variant is a gross deletion of the genomic region encompassing exon 23 and the first 19 nucleotides of exon 24 of the BRCA2 gene (c.8954-8_9136del). The 5' breakpoint of this deletion is within intron 22 at c.8954-8, and the 3' breakpoint is within exon 24 at c.9136. This creates a premature translational stop signal and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at