rs80359468
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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.4829_4830del(p.Val1610GlyfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,428 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: 0.0000034 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.721
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 13-32339181-CTG-C is Pathogenic according to our data. Variant chr13-32339181-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 51721.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339181-CTG-C is described in Lovd as [Pathogenic]. Variant chr13-32339181-CTG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.4829_4830del | p.Val1610GlyfsTer4 | 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.4829_4830del | p.Val1610GlyfsTer4 | frameshift_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 250066Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135536
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461428Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727042
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5
| 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 | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
| 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 | All of Us Research Program, National Institutes of Health | Dec 09, 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 detected in at least 9 individuals affected with breast or ovarian cancer and in an individual affected with pancreatic cancer (PMID: 12181777, 16455195, 16998791, 22798144, 29506128, 30014164, 30535581). This variant also has been reported as a recurrent mutation in suspected hereditary breast and ovarian cancer families in Brazil (PMID: 29907814, 30535581). This variant has been identified in 2/250066 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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 07, 2019 | proposed classification - variant undergoing re-assessment, contact laboratory - |
| 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 | Feb 12, 2020 | Variant summary: BRCA2 c.4829_4830delTG (p.Val1610GlyfsX4) 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 8e-06 in 250066 control chromosomes (gnomAD). c.4829_4830delTG has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (examples- Liede_2002, Ahn_2007, Alemar_2017, Palmero_2018, Rebbeck_2018). 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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 | Dec 06, 2023 | This sequence change creates a premature translational stop signal (p.Val1610Glyfs*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 (rs777265639, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 16455195, 21559243, 21607582, 25476495). ClinVar contains an entry for this variant (Variation ID: 51721). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Feb 27, 2020 | ACMG classification criteria: PVS1, PS4, PM2 - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | BRCA2: PVS1, PM2 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Liede et al., 2002; Rashid et al., 2006; Ahn et al., 2007; Kim et al., 2012; Rosenthal et al., 2014; Kang et al., 2015; Alemar et al., 2016; Barnes-Kedar et al., 2018; Cipriano et al., 2018; Lowery et al., 2018); 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 5057_5058delTG or 5055_5056delTG; This variant is associated with the following publications: (PMID: 21607582, 12181777, 27425403, 16455195, 21559243, 16998791, 25476495, 22798144, 25863477, 26187060, 26687385, 22340495, 26295337, 29346284, 29506128, 30014164, 30787465, 34645131, 30535581, 29161300, 29922827, 28888541, 30720243, 29907814) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 16, 2020 | This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 22798144 (2012), 21559243 (2011), 16455195 (2007), 30535581 (2019), 30720243 (2019), 30014164 (2018), 29907814 (2018), 29506128 (2018), 29446198 (2018), 29161300 (2017), and 25476495 (2015)). The frequency of this variant in the general population, 0.0001 (1/10048 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 28, 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 detected in at least 9 individuals affected with breast or ovarian cancer and in an individual affected with pancreatic cancer (PMID: 12181777, 16455195, 16998791, 22798144, 29506128, 30014164, 30535581). This variant also has been reported as a recurrent mutation in suspected hereditary breast and ovarian cancer families in Brazil (PMID: 29907814, 30535581). This variant has been identified in 2/250066 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 | clinical testing | Ambry Genetics | Jun 10, 2022 | The c.4829_4830delTG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 4829 to 4830, causing a translational frameshift with a predicted alternate stop codon (p.V1610Gfs*4). This mutation has been reported in multiple breast and/or ovarian cancer families to date (Ahn SH et al. Cancer Lett. 2007 Jan 8;245(1-2):90-5; Faroog A et al. J. Oncol. 2011 Mar;2011:632870; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134(3):1315-26), including multiple cohorts in Brazil (Alemar B et al. Cancer Genet. 2016 Sep;209(9):417-422; Alemar B et al. PLoS ONE. 2017 Nov;12:e0187630; Palmero EI et al. Sci Rep. 2018 Jun;8:9188; Cipriano NM et al. Breast Cancer. 2019 May;26:397-405). In one cohort of individuals undergoing BRCA1/2 testing at a commercial laboratory, approximately 40% of individuals with the c.4829_4830delTG mutation reported partial or full Ashkenazi Jewish ancestry (Rosenthal E et al. Breast Cancer Res. Treat. 2015 Jan;149(1):223-7), and in another study, this alteration was reported in both Ashkenazi and non-Ashkenazi Jewish breast cancer patients (Barnes-Kedar I et al. Breast Cancer Res. Treat. 2018 Nov;172:151-157). This alteration was reported in an individual diagnosed with pancreatic cancer (Lowery MA et al. J. Natl. Cancer Inst. 2018 Oct;110:1067-1074). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Of note, this alteration is also designated as 5057delTG 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. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 19, 2024 | - - |
Computational scores
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