rs80359605
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.6591_6592del(p.Glu2198AsnfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,457,504 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. T2197T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.14
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
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Very rare variant in population databases, with high coverage;
PP5
?
Variant 13-32340945-CTG-C is Pathogenic according to our data. Variant chr13-32340945-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 9319.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340945-CTG-C is described in Lovd as [Pathogenic]. Variant chr13-32340945-CTG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.6591_6592del | p.Glu2198AsnfsTer4 | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.6591_6592del | p.Glu2198AsnfsTer4 | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000406 AC: 1AN: 246418Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133330
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1457504Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 724738
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:31
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:11
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jan 26, 2016 | - - |
| 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 | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jun 15, 2023 | This sequence change creates a premature translational stop signal (p.Glu2198Asnfs*4) 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 (rs80359605, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 8524414, 16683254, 20736950, 21324516, 23569316, 26187060, 26219728). It has also been observed to segregate with disease in related individuals. This variant is also known as 6819delTG. ClinVar contains an entry for this variant (Variation ID: 9319). Therefore, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 21, 1995 | - - |
| 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 | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | May 26, 2023 | Criteria applied: PVS1,PS4,PM2_SUP - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 06, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jun 22, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Apr 07, 2022 | ACMG criteria used to clasify this variant: PVS1, PM2, PM1 - |
not provided Pathogenic:6
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Glu2198Asnfs*4 variant was identified in 12 of 8442 proband chromosomes (frequency: 0.001) from individuals or families with breast, prostate and pancreatic cancer (Edwards 2010, Gayther 1997, Hahn 2003, Mitra 2008,Nedelcu 2002, Zhang 2011, Zhang 2012, van der Hout 2006). The variant was also identified in dbSNP (ID: rs80359605) as “With Pathogenic allele”, Clinvitae database (pathogenic by ClinVar and Invitae), ARUP Laboratories BRCA Mutations Database (definitely pathogenic), the ClinVar database (pathogenic by Invitae, Ambry Genetics, GeneDx, QDNISJC, BIC,OMIM,SCRP), COGR database (pathogenic, by a clinical laboratories MESHWCR, QUEENSU and NYG ), the BIC database (48X with clinical importance), and UMD (18X with a “causal” classification). The p.Glu2198Asnfs*4 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2198 and leads to a premature stop codon 4 codons downstream. This alteration is then predicted to result in 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 | GeneKor MSA | Jan 01, 2020 | This sequence change deletes two nucleotides in exon 11 of the BRCA2 mRNA, causing a frameshift at codon 2198 and the creation of a premature translational stop signal 4 amino acid residues later. It is expected to result in an absent or disrupted protein product. This mutation has been described in individuals affected by breast, ovarian, and prostate cancer (PMID: 31043710, 26187060, 23569316). The mutation database contains entries for this variant (variation ID: 9319). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 14, 2020 | This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000034 (1/29204 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in affected individuals with breast, ovarian, and prostate cancers (PMIDs: 20736950 (2010), 21324516 (2011), 23569316 (2013), 26219728 (2016), 29371908 (2018), and 30702160 (2019)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 11, 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Wooster 1995, White 2001, Edwards 2010, Zhang 2011, Zhang 2012, Pritchard 2016, Pritzlaff 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as c.6819_6820delTG; This variant is associated with the following publications: (PMID: 27225637, 18182994, 28687356, 28008555, 11938448, 16683254, 17148771, 8988179, 29339979, 8524414, 21324516, 20736950, 11267991, 23318652, 21614564, 26219728, 12672316, 29371908, 11802209, 28724667, 23569316, 26187060, 25395318, 30078507, 30720243, 30702160, 30113427, 30199306, 31957001, 27433846, 32489267) - |
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 15, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
| 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 | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 19, 2021 | Variant summary: BRCA2 c.6591_6592delTG (p.Glu2198AsnfsX4) 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 allele was found at a frequency of 4.1e-06 in 246418 control chromosomes (gnomAD). c.6591_6592delTG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Gayther_1997, Meindl_2002, Nedelcu_2002, Risch_2006, Zhang_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 17 other ClinVar submitters (including 2 expert panels) have evaluated the variant after 2014 and cited it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | This sequence change creates a premature translational stop signal (p.Glu2198Asnfs*4) 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 (rs80359605, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 8524414, 16683254, 20736950, 21324516, 23569316, 26187060, 26219728). It has also been observed to segregate with disease in related individuals. This variant is also known as 6819delTG. ClinVar contains an entry for this variant (Variation ID: 9319). For these reasons, this variant has been classified as Pathogenic. - |
Breast and/or ovarian cancer Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jul 10, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 03, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 10, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 13, 2022 | The c.6591_6592delTG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 6591 to 6592, causing a translational frameshift with a predicted alternate stop codon (p.E2198Nfs*4). This alteration has been detected in multiple individuals with personal and/or family history consistent with hereditary breast and ovarian cancer (HBOC) syndrome; including diagnoses of breast cancer, prostate cancer, ovarian cancer, malignant pleural mesothelioma, and/or pancreatic cancer (Wooster R et al. Nature. 1995 Dec;378:789-92; Hahn SA et al. J. Natl. Cancer Inst. 2003 Feb;95:214-21; van der Hout AH et al. Hum. Mutat., 2006 Jul;27:654-66; Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Castro E et al. J. Clin. Oncol., 2013 May;31:1748-57; Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53; Betti M et al. Cancer Lett., 2017 10;405:38-45; Dominguez-Valentin M et al. Hered Cancer Clin Pract, 2018 Jan;16:4). Of note, this mutation is also designated as 6819delTG 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 | Feb 17, 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 reported in more than 10 individuals affected with breast, ovarian, or prostate cancer (PMID: 16683254, 21324516, 23569316, 26187060, 26219728, 27433846, 29371908, 32438681, 35908255). This variant has been identified in 1/246418 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. - |
Malignant tumor of prostate Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Apr 01, 2022 | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 13, 2023 | - - |
Endometrial carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Feb 21, 2023 | - - |
Computational scores
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Details are displayed if max score is > 0.2
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