rs869312761
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.9435_9436del(p.Ser3147CysfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,808 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: 0.0000075 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.347
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 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 13-32394863-CTG-C is Pathogenic according to our data. Variant chr13-32394863-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 38240.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32394863-CTG-C is described in Lovd as [Pathogenic]. Variant chr13-32394863-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.9435_9436del | p.Ser3147CysfsTer2 | frameshift_variant | 25/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.9435_9436del | p.Ser3147CysfsTer2 | frameshift_variant | 25/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251342Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135844
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GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461808Hom.: 0 AF XY: 0.00000688 AC XY: 5AN XY: 727204
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:26
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Oct 10, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 15, 2023 | This variant deletes 2 nucleotides in exon 25 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 several in individuals affected with breast or ovarian cancer (PMID: 8673090, 18489799, 21913181, 22798144, 24504028, 24549055, 25186627, 27153395, 27798748, 28008555). This variant has been identified in 1/251342 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, 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 | 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 06, 2023 | A known pathogenic mutation was detected in the BRCA2 gene (c.9435_9436delGT). This sequence change creates a premature translational stop signal (p.Ser3147Cysfs*2) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in gnomAD genomes. This variant has been reported in individuals affected with breast cancer (PMID: 8673090, 22798144, 18489799, 21913181), ovarian cancer (PMID: 24504028), and an individual with male breast cancer and melanoma (PMID: 28008555). This variant is also known as 9433delGT, 9663delGT and 3144_3145del in the literature. ClinVar contains an entry for this variant (Variation ID: 38240) with 17 submissions, all of which describe it as pathogenic, 3 stars, reviewed by expert panel. Lossof- function variants in BRCA2 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 18, 2015 | - - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Mar 06, 2024 | This variant has been identified by standard clinical testing. female patient with breast cancer Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 10, 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; 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; Observed in individuals with personal or family history of BRCA2-associated cancers (PMID: 8673090, 22798144, 24504028, 26962171); Also known as 9433delGT, 9663_9664delGT, and 9663delGT; This variant is associated with the following publications: (PMID: 30122538, 29922827, 28888541, 10570174, 15131399, 18489799, 8673090, 24504028, 22798144, 26962171, 28008555, 30293905, 21913181, 30720243, 31447099, 30787465, 33087929, 31892343, 31723001, 32295079, 33471991, 36623239, 34326862, 29446198, 20051372, 35186721, 35464868, 27798748, 24549055, 20104584, 19941162, 37528630) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 28, 2023 | PP5, PM2, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 25, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 21, 2021 | This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been described in families with hereditary breast and ovarian cancer syndrome and in individuals with breast cancer and/or ovarian cancer ((PMID: 29446198 (2018), 28008555 (2017), 27798748 (2017), 22798144 (2012), 21913181 (2012), 18489799 (2008), 8673090 (1996)). Based on the available information, this variant is classified as pathogenic. - |
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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 02, 2021 | Variant summary: BRCA2 c.9435_9436delGT (p.Ser3147CysfsX2) 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 251342 control chromosomes. c.9435_9436delGT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple 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.Ser3147Cysfs*2) 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 (rs80359763, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer and male breast cancer and melanoma (PMID: 8673090, 18489799, 21913181, 22798144, 24504028, 28008555). This variant is also known as 9433delGT, 9663delGT and 3144_3145del. ClinVar contains an entry for this variant (Variation ID: 38240). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 14, 2019 | The p.Ser3147CysfsX2 variant in BRCA2 has been reported in >20 individuals with breast cancer (Cunningham 2014, Phelan 1996, BIC database). It has also been identified in 1/113672 European chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 3147 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 38240). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 05, 2022 | This variant deletes 2 nucleotides in exon 25 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 several in individuals affected with breast or ovarian cancer (PMID: 8673090, 18489799, 21913181, 22798144, 24504028, 24549055, 25186627, 27153395, 27798748, 28008555). This variant has been identified in 1/251342 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 25, 2021 | The c.9435_9436delGT pathogenic mutation, located in coding exon 24 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 9435 to 9436, causing a translational frameshift with a predicted alternate stop codon (p.S3147Cfs*2). This mutation was first reported in a Canadian high-risk breast cancer family (Phelan CM et al. Nat. Genet. 1996 May;13:120-2). It has also been described in a Korean cohort of high-risk breast cancer families (Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26), as well as other HBOC families (Lubinski J et al. Fam. Cancer. 2004;3:1-10; Litton JK et al. Cancer. 2012 Jan;118:321-5). Of note, this alteration is also designated as 9433delGT and 9663delGT 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 | curation | Sema4, Sema4 | Nov 23, 2021 | - - |
Breast and/or ovarian cancer Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Dec 09, 2020 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
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 | May 16, 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 | Illumina Laboratory Services, Illumina | Aug 15, 2018 | The BRCA2 c.9435_9436delGT (p.Ser3147CysfsTer2) variant is a frameshift variant that is predicted to cause premature truncation of the protein. The p.Ser3147CysfsTer2 variant has been found in a heterozygous state in at least four patients with hereditary breast and ovarian cancer (HBOC), including in one male with breast cancer, in two individuals with breast and/or ovarian cancer and in one individual with ovarian cancer (Kim et al. 2012; Litton et al. 2012; Cunningham et al. 2014; Pritzlaff et al. 2017). The variant was also identified in a heterozygous state in three at-risk individuals with a family history of early-onset breast and ovarian cancer (Lubinski et al. 2004; Machackova et al. 2008; Bellacosa et al. 2010). This variant has not been described in the literature in patients with Fanconi anemia (FA), however, it is generally accepted that heterozygous variants pathogenic for HBOC confer carrier status for FA. Control data are unavailable for this variant which is reported at a frequency of 0.000009 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on one allele in a region of good sequence coverage so the variant is presumed to be rare. Based on the evidence and the potential impact of frameshift variants, the p.Ser3147CysfsTer2 variant is classified as pathogenic for BRCA2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 12, 2024 | - - |
Computational scores
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