rs80359462
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.4638delT(p.Phe1546fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000103 in 1,461,180 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: 0.000010 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.28
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 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 13-32338988-CT-C is Pathogenic according to our data. Variant chr13-32338988-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 37915.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338988-CT-C is described in Lovd as [Pathogenic]. Variant chr13-32338988-CT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.4638delT | p.Phe1546fs | frameshift_variant | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.4638delT | p.Phe1546fs | frameshift_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.4269delT | p.Phe1423fs | frameshift_variant | 11/27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.4638delT | non_coding_transcript_exon_variant | 10/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461180Hom.: 0 Cov.: 46 AF XY: 0.00000688 AC XY: 5AN XY: 726880
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:24
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | This variant deletes 1 nucleotide 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least five individuals affected with breast and/or ovarian cancer (PMID: 11044354, 14647210, 17148771, 25186627, 26296701, 33471991; Leiden Open Variation Database DB-ID BRCA2_002797) and one individual each affected with pancreatic and prostate cancer (PMID: 28873162, 29506128, 27433846). 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. - |
| 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 | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 24, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 09, 2021 | _x000D_ Criteria applied: PVS1, PS4, PM2_SUP - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 04, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 18, 2023 | 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 at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4866delT; This variant is associated with the following publications: (PMID: 25186627, 28888541, 14647210, 11044354, 15131399, 17148771, 26296701, 27433846, 21324516, 28873162, 29506128, 29961768, 31447099, 33654310, 32719484, 30787465, 29446198, 22762150, 33471991) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Feb 01, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 27, 2023 | The BRCA2 c.4638del; p.Phe1546LeufsTer22 variant (rs80359462), also known as 4866delT or 4862delT, is reported in individuals with breast, ovarian, prostate, or pancreatic cancer (Jakubowska 2003, Lowery 2018, Pritchard 2016, Tung 2015, Yurgelun 2019). This variant is classified as pathogenic by an expert review panel in ClinVar (Variation ID: 37915). It is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Jakubowska A et al. A high frequency of BRCA2 gene mutations in Polish families with ovarian and stomach cancer. Eur J Hum Genet. 2003 Dec;11(12):955-8. PMID: 14647210. Lowery MA et al. Prospective Evaluation of Germline Alterations in Patients With Exocrine Pancreatic Neoplasms. J Natl Cancer Inst. 2018 Oct 1;110(10):1067-1074. PMID: 29506128. Pritchard CC et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. PMID: 27433846. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. PMID: 25186627. Yurgelun MB et al. Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer. Genet Med. 2019 Jan;21(1):213-223. PMID: 29961768. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 28, 2024 | The BRCA2 c.4638del (p.Phe1546Leufs*22) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 26296701 (2015), 22762150 (2012), 21324516 (2011), 17148771 (2006)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 15, 2021 | DNA sequence analysis of the BRCA2 gene demonstrated a single base pair deletion in exon 11, c.4638del. This sequence change results in an amino acid frameshift and creates a premature stop codon 22 amino acids downstream of the change, p.Phe1546Leufs*22. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated BRCA2 protein with potentially abnormal function. The c.4638del sequence change has not been described in the gnomAD population database. This sequence change has previously been described in multiple individuals with BRCA2-related disorders (PMIDs: 11044354, 14647210, 17148771, 21324516, 26296701, 29506128). This variant is also known as 4862delT and 4866delT in the literature. Loss-of-function variants in BRCA2 are known to be pathogenic. Collectively this evidence suggests c.4638del is pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 20, 2023 | Variant summary: BRCA2 c.4638delT (p.Phe1546LeufsX22) 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. The variant was absent in 250140 control chromosomes (gnomAD). c.4638delT has been reported in the literature in several individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (e.g. Lubinski_2004, Jakubowska_2003, Ellingson_2015, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11044354, 26296701, 21702907, 14647210, 22762150, 15131399, 29446198, 17148771, 21324516). Multiple submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Phe1546Leufs*22) 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 ovarian cancer (PMID: 11044354, 14647210, 15131399, 17148771, 21324516, 26296701). This variant is also known as 4862delT and 4866delT. ClinVar contains an entry for this variant (Variation ID: 37915). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 29, 2023 | This variant deletes 1 nucleotide 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 reported in at least five individuals affected with breast and/or ovarian cancer (PMID: 11044354, 14647210, 17148771, 25186627, 26296701, 33471991; Leiden Open Variation Database DB-ID BRCA2_002797) and one individual each affected with pancreatic and prostate cancer (PMID: 28873162, 29506128, 27433846). 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. - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 25, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 15, 2021 | The c.4638delT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at position 4638, causing a translational frameshift with a predicted alternate stop codon (p.F1546Lfs*22). This mutation has been reported in a Polish ovarian and gastric cancer family (Jakubowska A et al. Eur J Hum Genet. 2003 Dec;11(12):955-8). It has also been reported in several other breast and ovarian cancer families (Br. J. Cancer 2000 Nov;83(10):1301-8; Lubinski J et al. Fam. Cancer 2004;3(1):1-10; Risch HA et al. J. Natl. Cancer Inst., 2006 Dec;98:1694-706; Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7; Tung N et al. Cancer, 2015 Jan;121:25-33; Ellingson MS et al. Breast Cancer Res. Treat. 2015 Aug). This alteration was also identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med., 2016 Aug;375:443-53). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Note that this alteration is also referred to as 4866delT and 4862delT in published literature. 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. - |
Breast and/or ovarian cancer Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Sep 19, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Mar 18, 2015 | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 09, 2023 | - - |
Computational scores
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SpliceAI score (max)
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