rs80359724
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.8673_8674del(p.Arg2892ThrfsTer14) variant causes a frameshift 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: 32)
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.41
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 13-32376709-CAA-C is Pathogenic according to our data. Variant chr13-32376709-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 52656.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32376709-CAA-C is described in Lovd as [Pathogenic]. Variant chr13-32376709-CAA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.8673_8674del | p.Arg2892ThrfsTer14 | frameshift_variant | 21/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8673_8674del | p.Arg2892ThrfsTer14 | frameshift_variant | 21/27 | 5 | NM_000059.4 | A2 |
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:16
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jul 02, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 18, 2018 | The BRCA2 c.8673_8674delAA; p.Arg2892fs variant (rs80359724), is not reported in the medical literature but is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 52656). This variant is also absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant deletes two nucleotides causing a frameshift, and is predicted to result in a truncated protein or absent transcript. Based on the above information, this variant is considered pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 22, 2015 | This deletion of 2 nucleotides in BRCA2 is denoted c.8673_8674delAA at the cDNA level and p.Arg2892ThrfsX14 (R2892TfsX14) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 8901delAA. The normal sequence, with the bases that are deleted in braces, is TAAC[AA]GACA. The deletion causes a frameshift, which changes an Arginine to a Threonine at codon 2892, and creates a premature stop codon at position 14 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. We consider this variant to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 24, 2015 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Sep 08, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
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 | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 09, 2023 | This sequence change creates a premature translational stop signal (p.Arg2892Thrfs*14) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 52656). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 12, 2021 | Variant summary: BRCA2 c.8673_8674delAA (p.Arg2892ThrfsX14) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251318 control chromosomes. c.8673_8674delAA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters, including two expert panels (evaluation after 2014) have cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 24, 2020 | The c.8673_8674delAA pathogenic mutation, located in coding exon 20 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 8673 to 8674, causing a translational frameshift with a predicted alternate stop codon (p.R2892Tfs*14). This mutation was identified in two individuals as part of a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 15, 2023 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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