rs1555288462
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.9014_9017dupGATA(p.Tyr3006fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
BRCA2
NM_000059.4 frameshift, stop_gained
NM_000059.4 frameshift, stop_gained
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.75
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 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-32379808-G-GAGAT is Pathogenic according to our data. Variant chr13-32379808-G-GAGAT is described in ClinVar as [Pathogenic]. Clinvar id is 433834.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.9014_9017dupGATA | p.Tyr3006fs | frameshift_variant, stop_gained | 23/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.9014_9017dupGATA | p.Tyr3006fs | frameshift_variant, stop_gained | 23/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.8645_8648dupGATA | p.Tyr2883fs | frameshift_variant, stop_gained | 23/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*1072_*1075dupGATA | non_coding_transcript_exon_variant | 22/26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259.2 | n.*1072_*1075dupGATA | 3_prime_UTR_variant | 22/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Dec 15, 2017 | Variant allele predicted to encode a truncated non-functional protein. - |
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Tyr3006X duplication variant was not identified in the literature but was identified in the UMD (2X as a causal variant). Another variant with the same change at the protein level (c.9018C>A, p.Tyr3006X) was identified by Diez (2003) in 2 of 1268 proband chromosomes (frequency: 0.002) from Spanish individuals or families with breast or ovarian cancer, and was also identified in HGMD, LOVD and the BIC database (1X as a clinically important variant). The p.Tyr3006X duplication variant leads to a premature stop codon at position 3006, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at