rs80359705
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.8297del(p.Thr2766AsnfsTer11) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000112 in 1,613,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T2766T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.8297del | p.Thr2766AsnfsTer11 | frameshift_variant | 18/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8297del | p.Thr2766AsnfsTer11 | frameshift_variant | 18/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461780Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7AN XY: 727184
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152178Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74336
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 06, 2024 | This variant deletes 1 nucleotide in exon 18 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 9 individuals affected with breast or ovarian cancer (PMID: 10682686, 12960223, 23146383, 25682074, 26681312, 26845104, 33471991), 3 individuals affected with prostate cancer (PMID: 20736950, 23569316), and 1 unaffected individual (PMID: 33471991). This variant has been identified in 70 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. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 1996 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
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, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
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 | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Apr 16, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 10, 2024 | This sequence change creates a premature translational stop signal (p.Thr2766Asnfs*11) 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, ovarian and/or prostate cancer (PMID: 8589730, 10682686, 12960223, 20736950, 23028338, 25085752, 26681312). This variant is also known as 8525delC. ClinVar contains an entry for this variant (Variation ID: 38149). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 01, 2016 | Variant summary: The BRCA2 c.8297delC (p.Thr2766Asnfs) 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. The variant of interest was not found in controls (ExAC, 1000 Gs or ESP). Multiple publications cite the variant in affected individuals, along with multiple reputable databases/clinical laboratories citing the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is 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 | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 22, 2018 | The p.Thr2766AsnfsX11 (NM_000059.3 c.8297delC) variant in BRCA2 (also referred t o as c.8285delC in the literature) has been previously reported in many individu als and families with breast, ovarian or prostate cancer (Tavtigian 1996, Castro 2013, McVeigh 2014, Wong-Brown 2015), and was absent from large population stud ies. In addition, this variant was classified as Pathogenic by the ClinGen-appr oved ENIGMA expert panel (ClinVar SCV000282457.1). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 2766 and leads to a premature termination codon 11 amino acids downstre am. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 function is an established disease mechanism in here ditary breast and ovarian cancer syndrome (HBOC). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant m anner based on its occurrence in affected individuals and its predicted impact t o the protein. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate, PP5 (Richards 2015). - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 22, 2023 | The BRCA2 c.8297del; p.Thr2766AsnfsTer11 variant (rs80359705), also known as 8525delC, is reported in individuals with hereditary breast and ovarian cancer syndrome (Edwards 2010, Lilyquist 2017, Tavtigian 1996). This variant is also reported in ClinVar (Variation ID: 38149). It is absent from the 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: Edwards SM et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010 Sep 7;103(6):918-24. PMID: 20736950. Lilyquist J et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017 Nov;147(2):375-380. PMID: 28888541. Tavtigian SV et al. The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds. Nat Genet. 1996 Mar;12(3):333-7. PMID: 8589730. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 13, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 12, 2023 | The BRCA2 c.8297del (p.Thr2766Asnfs*11) variant has been reported in the published literature in individuals and families affected with breast and/or ovarian cancer (PMIDs: 8589730 (1996), 10682686 (2000), 26681312 (2015)) and prostate cancer (PMIDs: 20736950 (2010), 23569316 (2013)). The frequency of this variant in the general population, 0.0000066 (1/152178 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 27, 2022 | 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; Observed in individuals with a personal and/or family history of BRCA2-related cancers (Tavtigian 1996, Evans 2003, Edwards 2010, Willems-Jones 2012, McVeigh 2014, Pritzlaff 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8525delC; This variant is associated with the following publications: (PMID: 12474142, 20736950, 12960223, 30609409, 12181777, 26046366, 25682074, 26681312, 23035815, 23884708, 8589730, 23028338, 28008555, 25085752, 22703879, 26845104, 31090900, 26295337, 25685387, 23569316, 10682686, 31569370, 32853339, 30787465, 33087929) - |
Hereditary cancer-predisposing syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | May 23, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 23, 2021 | The c.8297delC pathogenic mutation, located in coding exon 17 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 8297, causing a translational frameshift with a predicted alternate stop codon (p.T2766Nfs*11). This mutation was reported in one family with multiple cases of female and male breast cancer and ovarian cancer (Tavtigian SV et al. Nat. Genet. 1996 Mar;12:333-7). This alteration has also been reported in multiple men diagnosed with prostate cancer before the age of 55 (Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; Willems-Jones A et al. BJU Int. 2012 Dec;110:E1181-6; Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57). Of note, this alteration is also designated as 8525delC 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 20, 2023 | This variant deletes 1 nucleotide in exon 18 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 9 individuals affected with breast or ovarian cancer (PMID: 10682686, 12960223, 23146383, 25682074, 26681312, 26845104, 33471991), 3 individuals affected with prostate cancer (PMID: 20736950, 23569316), and 1 unaffected individual (PMID: 33471991). This variant has been identified in 70 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. - |
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 01, 2021 | - - |
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 | Mar 15, 2022 | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
BRCA2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 16, 2023 | The BRCA2 c.8297delC variant is predicted to result in a frameshift and premature protein termination (p.Thr2766Asnfs*11). This variant (also known as 8525delC) has been reported in individuals with breast, ovarian, or prostate cancer (Table 1, Tavtigian et al. 1996. PubMed ID: 8589730; Table 1, Edwards et al. 2003. PubMed ID: 12474142; Table 1, Edwards et al. 2010. PubMed ID: 20736950, Table 2, Wong-Brown et al. 2015. PubMed ID: 25682074; Table S7, Lilyquist et al. 2017. PubMed ID: 28888541). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant has been reviewed by an expert panel and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38149/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 12, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at