chr13-32380135-G-GA
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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.9253dupA(p.Thr3085fs) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.00000206 in 1,458,716 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift, splice_region
NM_000059.4 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.00
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 13-32380135-G-GA is Pathogenic according to our data. Variant chr13-32380135-G-GA is described in ClinVar as [Pathogenic]. Clinvar id is 38225.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.9253dupA | p.Thr3085fs | frameshift_variant, splice_region_variant | 24/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.9253dupA | p.Thr3085fs | frameshift_variant, splice_region_variant | 24/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.8884dupA | p.Thr2962fs | frameshift_variant, splice_region_variant | 24/27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.*1311dupA | splice_region_variant, non_coding_transcript_exon_variant | 23/26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000614259.2 | n.*1311dupA | 3_prime_UTR_variant | 23/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1458716Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 725646
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GnomAD4 genome
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:29
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:12
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
| Likely pathogenic, no assertion criteria provided | research | deCODE genetics, Amgen | Jul 21, 2023 | The variant NM_000059.4:c.9253dup (chr13:32380135) in BRCA2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jun 16, 2014 | - - |
| 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 | 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) | Dec 11, 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 | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Apr 27, 2018 | The c.9246_9247dupA (p.Thr3085Asnfs*26) frameshift variant in BRCA2 has been reported in multiple unrelated patients with breast, ovarian or prostate cancer [PMID 11389159, 16455195, 16683254, 21952622,22798144, 25330149]. Based on the current evidence, this variant is classified as pathogenic - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
not provided Pathogenic:6
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 11, 2020 | This frameshift variant causes the premature termination of BRCA2 protein synthesis. In the published literature, it has been reported in individuals affected with breast and/or ovarian cancer, prostate cancer, and esophageal cancer (PMIDs: 11389159 (2001), 21952622 (2011), 22798144 (2012), 29915322 (2018), 30322717 (2018), 31396961 (2019), 30702160 (2019), and 30972954 (2019)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); Also known as 9481insA, 9481dupA, and 9474insA; This variant is associated with the following publications: (PMID: 22798144, 23034506, 16455195, 26287763, 21120943, 25330149, 30702160, 30322717, 32854451, 23569316, 11920643, 20104584, 19656164, 18824701, 11389159, 16683254, 21952622, 26681312, 25863477, 22720145, 28008555, 27836010, 28152038, 11802209, 7627958, 30972954, 29310832, 28724667, 29915322, 29339979, 30720243, 31396961, 29625052, 31447099, 32832836) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Thr3085AsnfsX26 variant was identified in 13 of 20330 proband chromosomes (frequency: 0.0006) from German, Danish, Korean, American, and British individuals or families with (sporadic, high risk, early onset, or male) breast cancer, sporadic or familial ovarian cancer or prostate cancer (Meindl_2002_11802209, Bergthorsson_2001_11389159, Kang_2015_25863477 , Kim_2012_22798144, Pal_2015_26287763 , Pritzlaff_2016_28008555, Kote-Jarai_2011_21952622, Rebbeck_2016_27836010, Borg_2010_20104584, Cybulski_2015_25330149). In a study looking at transheterozygosity (inheritance of pathogenic mutations in both BRCA1 and BRCA2), the variant was identified in 1 Italian proband with breast cancer, co-occurring with BRCA1 c.3228_3229delAG (Rebbeck_2016_27836010). The variant was also identified in dbSNP (ID: rs80359752) “With Pathogenic allele”, ClinVar (classified pathogenic, reviewed by an expert panel (2016); submitters: pathogenic by ENIGMA, CIMBA, Fulgent Genetics, Ambry Genetics, GeneDx, Color Genomics Inc, Quest Diagnostics Nichols Institute San Juan Capistrano, Invitae, Dept. of Medical Genetics (Oslo University Hospital), BIC and SCRP (Sharing Clinical Reports Project); and likely pathogenic by Counsyl), Clinvitae (4x), GeneInsight-COGR (classified pathogenic by 2 clinical laboratories), LOVD 3.0 (1x), UMD-LSDB (5x causal), BIC Database (19x, with clinical importance, class 5 (pathogenic)), ARUP Laboratories (5-definitely pathogenic), Zhejiang Colon Cancer Database; the variant was not identified in Cosmic, MutDB, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.9253dupA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3085 and leads to a premature stop codon at position 3110. 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, no assertion criteria provided | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
| 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 14, 2020 | Variant summary: BRCA2 c.9253dupA (p.Thr3085AsnfsX26) 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 4e-06 in 248942 control chromosomes. c.9253dupA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Bergthorsson_2001, Inoue_1997, Kim_2012, Pal_2015, Rebbeck_2016). These data indicate that the variant is very likely to be associated with disease. At-least one trans heterozygous co-occurrence with another pathogenic variant has been reported (BRCA1 c.3226_3227AG (reported as NM_007294:c.3228_3229delAG), p.Gly1077fs) (Rebbeck_2016). Thirteen clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters 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 | Jan 18, 2024 | This sequence change creates a premature translational stop signal (p.Thr3085Asnfs*26) 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 (rs80359752, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 11389159, 16455195, 16683254, 19656164, 21952622, 22798144, 23569316, 25330149). This variant is also known as 9474insA, 9481insA, 9253insA, and c.9253_9254insA. ClinVar contains an entry for this variant (Variation ID: 38225). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 14, 2024 | The c.9253dupA (p.T3085Nfs*26) alteration, located in exon 24 (coding exon 23) of the BRCA2 gene, consists of a duplication of A at position 9253, causing a translational frameshift with a predicted alternate stop codon after 26 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration was flagged as a low confidence call in the Genome Aggregation Database (gnomAD). This alteration has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Bergthorsson, 2001; Meindl, 2002; Kim, 2012; Kang, 2015; Pal, 2015). This mutation has also been detected in a male with early-onset prostate cancer (Kote-Jarai, 2011) and in a male breast cancer patient (Pritzlaff, 2017). Of note, this alteration is also designated as c.9253insA, c.9253_9254insA, and c.9474insA in published literature. Based on the available evidence, this alteration is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 22, 2022 | This variant inserts 1 nucleotide in exon 24 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 9246_9247insA, 9474insA and 9481insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals and families affected with breast and/or ovarian cancer (PMID: 11389159, 16683254, 20104584, 22798144, 25330149, 25863477, 26287763, 28008555, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001724) and two individuals affected with prostate cancer (PMID: 23569316). This variant has been identified in 2/243602 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. - |
BRCA2-related cancer predisposition Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 28, 2024 | This variant inserts 1 nucleotide in exon 24 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 9246_9247insA, 9474insA and 9481insA in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals and families affected with breast and/or ovarian cancer (PMID: 11389159, 16683254, 20104584, 22798144, 25330149, 25863477, 26287763, 28008555, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001724) and two individuals affected with prostate cancer (PMID: 23569316). This variant has been identified in 2/243602 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. - |
BRCA2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 24, 2024 | The BRCA2 c.9253dupA variant is predicted to result in a frameshift and premature protein termination (p.Thr3085Asnfs*26). This variant (also reported as 9253insA, 9481dupA & 9474insA) has been reported in many individuals with various cancers, including breast/ovarian cancer (Bergthorsson et al. 2001. PubMed ID: 11389159; Table S1, Borg et al. 2010. PubMed ID: 20104584; Table 4, Kim et al. 2012. PubMed ID: 22798144; Table S1, Carter et al. 2018. PubMed ID: 30322717), prostate cancer (Table A1, Castro et al. 2013. PubMed ID: 23569316; Table S2, Matejcic et al. 2020. PubMed ID: 32832836), biliary tract cancer (Power et al. 2020. PubMed ID: 32918181), lung and esophageal squamous cell carcinoma (Table S2A, Huang et al. 2018. PubMed ID: 29625052), and renal cell carcinoma (Yngvadottir et al. 2022. PubMed ID: 35441217). It has also been reported as pathogenic by multiple sources in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38225/). This variant is reported in 0.00089% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 21, 2024 | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 07, 2024 | - - |
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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