rs80359377
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.3199del(p.Thr1067LeufsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,658 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: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.717
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 13-32337553-TA-T is Pathogenic according to our data. Variant chr13-32337553-TA-T is described in ClinVar as [Pathogenic]. Clinvar id is 51421.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337553-TA-T is described in Lovd as [Pathogenic]. Variant chr13-32337553-TA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.3199del | p.Thr1067LeufsTer10 | 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.3199del | p.Thr1067LeufsTer10 | frameshift_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1455658Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 723368
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:22
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6
| 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) | May 29, 2002 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jan 21, 2011 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Feb 28, 2019 | The c.3199delA (p.Thr1067Leufs*10) variant in the BRCA2 gene is predicted to introduce a premature translational termination codon. This variant has been observed in a Polish family affected with hereditary breast and ovarian cancer (PMID 15146557) and an individual affected with triple negative breast cancer (PMID 25452441). This variant has never been observed in general population databases. Therefore, we classify this c.3199delA (p.Thr1067Leufs*10) variant in the BRCA2 gene as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jul 15, 2022 | - - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 09, 2020 | 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 et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Gorski 2004, Lubinski 2004, Couch 2015); This variant is associated with the following publications: (PMID: 15146557, 25452441, 26843898, 24156927, 15131399, 26848151, 28324225, 28135145, 28492532) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 29, 2022 | This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant 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 (PMID: 33471991 (2021), 25452441 (2015)), 15146557 (2004)), colorectal cancer (PMID: 28135145 (2017)) and ampullary cancer (PMID: 28135145 (2016)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Jun 14, 2022 | PVS1, PS4, PM2_SUP - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 14, 2021 | 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 detected in at least five individuals affected with breast and/or ovarian cancer (PMID: 25452441, 26843898, 28324225, 33471991; Leiden Open Variation Database DB-ID BRCA2_004463) and suspected hereditary breast and ovarian cancer families (PMID: 15131399, 15146557, 24156927). 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 | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jul 12, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 07, 2021 | The c.3199delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 3199, causing a translational frameshift with a predicted alternate stop codon (p.T1067Lfs*10). This mutation has been identified in multiple individuals/families with hereditary breast and ovarian cancer (HBOC) syndrome (Górski B et al. Int. J. Cancer. 2004 Jul;110:683-6; Lubinski J et al. Fam. Cancer. 2004;3:1-10; Tea MK et al. Maturitas. 2014 Jan;77:68-72; Couch FJ et al. J Clin Oncol, 2015 Feb;33:304-11; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in a patient with an ampullary tumor (Villalona-Calero MA et al. J Natl Cancer Inst, 2016 Jul;108). Of note, this alteration is also designated as 3427delA 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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 06, 2023 | This sequence change creates a premature translational stop signal (p.Thr1067Leufs*10) 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 a personal and/or family history of hereditary breast and ovarian cancer as well as colorectal cancer (PMID: 15146557, 24156927, 25452441, 28135145). This variant is also known as 3427delA. ClinVar contains an entry for this variant (Variation ID: 51421). 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 | Sep 03, 2024 | Variant summary: BRCA2 c.3199delA (p.Thr1067LeufsX10), also reported as c.3427delA, 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 247034 control chromosomes. c.3199delA has been reported in the literature in at least 1 individual affected with clinical features of Hereditary Breast And Ovarian Cancer Syndrome (example, Agaoglu_2021). The following publication has been ascertained in the context of this evaluation (PMID: 34637943). ClinVar contains an entry for this variant (Variation ID: 51421). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Immunology and Genetics Kaiserslautern | Jul 02, 2024 | ACMG Criteria: PVS1, PM2, PP5_m; Variant was found in heterozygous state - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 25, 2024 | Criteria applied: PVS1,PM5_STR,PM2_SUP - |
Familial cancer of breast Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 26, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
BRCA2-related cancer predisposition Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 25, 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 detected in at least five individuals affected with breast and/or ovarian cancer (PMID: 25452441, 26843898, 28324225, 33471991; Leiden Open Variation Database DB-ID BRCA2_004463) and suspected hereditary breast and ovarian cancer families (PMID: 15131399, 15146557, 24156927). 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 carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 20, 2021 | Invasive Ductal Carcinoma Estrogen Receptor: Positive Progesterone Receptor: Positive HER2 Receptor: Positive - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at