13-32340037-C-G
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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.5682C>G(p.Tyr1894Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Y1894Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 stop_gained
NM_000059.4 stop_gained
Scores
1
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5
Clinical Significance
Conservation
PhyloP100: 0.349
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 13-32340037-C-G is Pathogenic according to our data. Variant chr13-32340037-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 37989.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340037-C-G is described in Lovd as [Pathogenic]. Variant chr13-32340037-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.5682C>G | p.Tyr1894Ter | stop_gained | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.5682C>G | p.Tyr1894Ter | stop_gained | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 152044Hom.: 0 Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:43
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:16
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 22, 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) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a 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 18 individuals affected with breast and/or ovarian cancer (PMID: 11179017, 16168118, 18042939, 17972171, 20104584, 25682074, 25927356, 26219728, 26687385, 27741520, 28294317, 28724667, 28831036, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001092): and in individuals affected with pancreatic, prostate and colorectal cancer (PMID: 20736950, 29360161, 29478780). This variant also has been reported in related individuals affected with Fanconi anemia (PMID: 15070707). This variant has been identified in 1/250362 chromosomes 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, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jul 19, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 28, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 02, 2021 | - - |
| Pathogenic, criteria provided, single submitter | research | UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill | Sep 07, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 07, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 08, 2014 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 29, 2015 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:7
| 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 | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | This sequence change creates a premature translational stop signal (p.Tyr1894*) 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 present in population databases (rs41293497, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer, breast cancer, prostate cancer, and Fanconi anemia (PMID: 11179017, 15070707, 16168118, 18042939, 20736950). This variant is also known as 5910C>G. ClinVar contains an entry for this variant (Variation ID: 37989). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Aug 13, 2018 | The c.5682C>G (p.Tyr1894*) variant in the BRCA2 gene is located on the exon 11 and is predicted to introduce a premature translation termination codon (p.Tyr1894*), resulting in an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832). This variant has been reported in more than 10 unrelated individuals with breast or ovarian cancer (PMID: 35912179, 31528241, 26852015, 31837001, 33113089, 36119527). This variant is reported in ClinVar as pathogenic (ID: 37989) and reviewed by the expert panel. This variant is rare in the general population according to gnomAD (1/250362). Therefore, the c.5682C>G (p.Tyr1894*) variant of BRCA2 has been classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 14, 2019 | The p.Tyr1894X (c.5682C>G) variant in BRCA2 has been reported in >20 individuals with BRCA2-related cancers (Risch 2001, Edwards 2010, Tea 2014, Alemar 2017, AlDubayan 2018, Dudley 2018, BIC database). Furthermore, another variant at this position resulting in the same amino acid change (c.5681dup, p.Tyr1894X) is classified as pathogenic for hereditary breast and ovarian cancer (HBOC) by our laboratory. The c.5682C>G variant has also been identified in 0.001% (1/113148) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of HBOC in the general population. This nonsense variant is predicted to lead to a premature termination codon at position 1894, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in HBOC. Finally, the p.Tyr1894X (c.5682C>G) variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37989). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4, PS1. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 14, 2016 | Variant summary: The BRCA2 c.5682C>G (p.Tyr1894X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g.c.6644_6647delACTC, c.6682dupG, c.6997_6998delGT, etc.). This variant is absent in 120576 control chromosomes from ExAC. This variant is a recurrent pathogenic mutation found in several HBOC patients/families and in individuals undergoing BRCA1/2 clinical testing. In compound heterozygous with another variant, it has also been reported to cause Fanconi Anemia. Several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as a Disease Variant (or Pathogenic). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
not provided Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 20, 2023 | Nonsense 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; Identified in individuals with a personal or family history consistent with pathogenic variants in this gene (Risch et al., 2001; Pohlreich et al., 2005; Edwards et al., 2010; Cini et al., 2016; Fernandes et al., 2016; Kim et al., 2016; Dudley et al., 2018); Not observed at a 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 5910C>G; This variant is associated with the following publications: (PMID: 20736950, 29446198, 29339979, 29360161, 32211327, 29922827, 28888541, 24055113, 25525159, 11897832, 11179017, 27003155, 24156927, 26852015, 25637381, 26852130, 26219728, 25682074, 26848529, 27225637, 27741520, 27836010, 28176296, 28294317, 27356891, 28724667, 28423363, 29478780, 29907814, 29909963, 16168118, 29161300, 30720243, 19471317, 17972171, 18042939, 15340362, 15070707, 31174498, 31528241, 20104584, 30702160, 32467295, 34399810, 11597388, 32318955, 32521533, 31447099, 32101877, 31825140, 32885271, 30787465, 33087929, 33804961) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 13, 2023 | This nonsense variant causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/250362 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals/families with breast cancer (PMID: 18042939 (2007), 28724667 (2017), 29907814 (2018), 31174498 (2019), 32029870 (2020)), ovarian cancer (PMID: 1179017 (2001)), prostate cancer (PMID: 20736950 (2010)), gastric cancer (PMID: 32521533 (2020)), and liver cancer (PMID: 34399810 (2021)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Tyr1894* variant was identified in 18 of 8970 proband chromosomes (frequency: 0.002) from Chinese, Italian, and Czech individuals or families with breast, ovarian and prostate cancers and was not identified in 182 control chromosomes from healthy individuals (Cini 2016, Cao WM, Risch 2001, Edwards 2010, Pohlreich 2005, Borg 2010, Caux-Moncoutier 2009). The variant was also identified in dbSNP (ID: rs41293497) as “With Likely benign, Pathogenic allele”, and in the NHLBI GO Exome Sequencing Project in 1 of 8596 European American alleles (frequency: 0.0001). The variant was identified in ClinVar (classified as pathogenic by ENIGMA, GeneDX, Invitae, Ambry Genetics, and five other submitters). In addition, the variant was identified as pathogenic in the COGR database by Women’s College Hospital, Children’s’ Hospital of Eastern Ontario, Kingston General Hospital – Queen’s University and North York General Hospital. The variant was also identified by our laboratory in three individuals with breast and basal cell carcinomas, in the BIC database (67x as Class 5 with clinical importance), and in the ARUP Laboratories BRCA Mutations Database (as definitely pathogenic). The variant was not identified in COSMIC, the Fanconi Anemia Mutation Database (LOVD), the 1000 Genomes Project, or the Exome Aggregation Consortium database (August 8, 2016). The p.Tyr1894* variant leads to a premature stop codon at position 1894, 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 22, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2022 | BRCA2: PVS1, PM2 - |
Hereditary cancer-predisposing syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2022 | The p.Y1894* pathogenic mutation (also known as c.5682C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 5682. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) cohorts (Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Marroni F et al. Eur J Hum Genet, 2004 Nov;12:899-906; Pohlreich P et al. Breast Cancer Res. 2005 Jul;7:R728-36; Borg A et al. Hum Mutat, 2010 Mar;31:E1200-40; Tea MK et al. Maturitas, 2014 Jan;77:68-72; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Lang GT et al. Int. J. Cancer 2017 Jul;141(1):129-142; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Alemar B et al. PLoS One, 2017 Nov;12:e0187630; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Wu H et al. Hum Hered, 2019 Feb;84:160-169; Cao WM et al. BMC Cancer, 2019 Jun;19:551; Guo X et al. Int J Cancer, 2020 04;146:2175-2181; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473; Meng H et al. Int J Cancer, 2020 06;146:3044-3052; Liu Y et al. J Hematol Oncol, 2021 01;14:18; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879), including patients with male breast cancer (Tai YC et al. J Natl Cancer Inst, 2007 Dec;99:1811-4). This mutation has also been reported in individuals with prostate, pancreatic, colorectal and gastric cancers (Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; AlDubayan SH et al. Am J Hum Genet, 2018 03;102:401-414; Dudley B et al. Cancer, 2018 04;124:1691-1700; Wei Y et al. Oncologist, 2020 07;25:e1042-e1050; Zhou J et al. Oncology, 2020 Jun;98:583-588), as well as in members of one Fanconi anemia family (Wagner JE et al. Blood, 2004 Apr;103:3226-9). 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 | curation | Sema4, Sema4 | Mar 14, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 16, 2022 | This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a 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 18 individuals affected with breast and/or ovarian cancer (PMID: 11179017, 16168118, 18042939, 17972171, 20104584, 25682074, 25927356, 26219728, 26687385, 27741520, 28294317, 28724667, 28831036, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001092): and in individuals affected with pancreatic, prostate and colorectal cancer (PMID: 20736950, 29360161, 29478780). This variant also has been reported in related individuals affected with Fanconi anemia (PMID: 15070707). This variant has been identified in 1/250362 chromosomes 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 | research | Academic Department of Medical Genetics, University of Cambridge | Jan 26, 2018 | Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. - |
Breast and/or ovarian cancer Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 03, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Nov 23, 2015 | - - |
Familial cancer of breast Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 01, 2024 | - - |
Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 11, 2021 | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 15, 2024 | Criteria applied: PVS1,PM5_STR - |
Medulloblastoma;C0040588:Tracheoesophageal fistula;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 18, 2017 | - - |
Ovarian cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
BRCA2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 17, 2024 | The BRCA2 c.5682C>G variant is predicted to result in premature protein termination (p.Tyr1894*). This variant has been documented to be causative for multiple cancers including breast, ovarian and prostate (see for example - Risch et al. 2001. PubMed ID: 11179017; Edwards et al. 2010. PubMed ID: 20736950; Dudley et al. 2018. PubMed ID: 29360161). In at least one individual this variant was reported in the compound heterozygous state in an individual with Fanconi anemia (Wagner et al. 2004. PubMed ID: 15070707). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted in ClinVar as pathogenic by multiple submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/37989/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Ovarian neoplasm Pathogenic:1
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at