rs80359512
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.5410_5411del(p.Val1804LysfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.06
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 13-32339763-CTG-C is Pathogenic according to our data. Variant chr13-32339763-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 37963.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339763-CTG-C is described in Lovd as [Pathogenic]. Variant chr13-32339763-CTG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.5410_5411del | p.Val1804LysfsTer2 | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5410_5411del | p.Val1804LysfsTer2 | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461654Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727118
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 20, 2017 | The p.Val1804fs variant in BRCA2 has been reported in 6 individuals with heredit ary breast and/or ovarian cancer (HBOC; Marroni 2004, Breast Cancer Information Core (BIC) database; https://research.nhgri.nih.gov/projects/bic/) and was absen t from large population studies, though the ability of these studies to accurate ly detect indels may be limited. This variant is predicted to cause a frameshift , which alters the protein?s amino acid sequence beginning at position 1804 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss o f function of the BRCA2 gene is an established disease mechanism in HBOC. In add ition, this variant was classified as pathogenic on Sept 8, 2016 by the ClinGen- approved ENIGMA expert panel (ClinVar SCV000300872.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based on predicted impact to the protein and absence from controls. - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This frameshifting variant in exon 11 of 28 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with breast and/or ovarian cancer (PMID: 15340362, 12048272, 28525389) and pancreatic cancer (PMID: 24963353). This variant is also known as 5638delGT in the literature. It is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.5410_5411del (p.Val1804LysfsTer2) variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Val1804Lysfs*2) 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 premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15340362, 24963353). This variant is also known as 5638delGT. ClinVar contains an entry for this variant (Variation ID: 37963). 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 | May 04, 2022 | Variant summary: BRCA2 c.5410_5411delGT (p.Val1804LysfsX2) 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 251140 control chromosomes. c.5410_5411delGT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4
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, 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, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 30, 2007 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 12, 2021 | This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer, pancreatic cancer, and ovarian cancer (PMIDs: 33888336 (2021), 32563252 (2020), 32194909 (2020), 29446198 (2018), 28525389 (2017), 24963353 (2014)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 16, 2020 | PVS1, PM2, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 10, 2021 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with personal or family history of BRCA2-related cancers (Euhus 2002, Marroni 2004, Johns 2014, Meeks 2016); Also known as 5638delGT or 5638_5639delGT; This variant is associated with the following publications: (PMID: 15340362, 31447099, 26586665, 24963353, 12048272, 32194909) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 29, 2021 | The c.5410_5411delGT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 5410 to 5411, causing a translational frameshift with a predicted alternate stop codon (p.V1804Kfs*2). This alteration has been identified in several breast/ovarian cohorts and in a 56-year-old Australian female with pancreatic cancer (Marroni F et al. Eur. J. Hum. Genet. 2004 Nov;12(11):899-906; Johns A et al. Genome Med. 2014 May 29;6(5):42; Meeks HD et al. J. Natl. Cancer Inst. 2016 Feb;108(2); Dougherty BA et al. Oncotarget, 2017 Jul;8:43653-43661). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note, this alteration is also designated as 5638delGT in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 21, 2023 | This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been detected in 2 individuals affected with ovarian cancer (PMID: 28525389, 33888336), 2 individuals affected with pancreatic cancer (PMID: 24963353, 32194909), an individual from a cohort affected with BRCA-associated cancer (PMID: 32699032), in a suspected hereditary breast and ovarian cancer family (PMID: 15340362), and in 20 families among the CIMBA participants (PMID: 29446198). 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 and/or ovarian cancer Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jun 28, 2010 | - - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 12, 2022 | - - |
Computational scores
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