rs80359392
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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.3599_3600del(p.Cys1200Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,754 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: 0.000016 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.187
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 13-32337952-CTG-C is Pathogenic according to our data. Variant chr13-32337952-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 51493.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337952-CTG-C is described in Lovd as [Pathogenic]. Variant chr13-32337952-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.3599_3600del | p.Cys1200Ter | 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.3599_3600del | p.Cys1200Ter | frameshift_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251042Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135738
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GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461754Hom.: 0 AF XY: 0.0000110 AC XY: 8AN XY: 727162
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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:9
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
| 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, 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 | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 10, 2014 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Cys1200X variant was identified by De Leon Matsuda (2002) in one individual with breast cancer and in one control subject with a “suspicious breast mass” which was interpreted as fibrocystic disease, though a biopsy was not taken from the control subject. The variant was also identified in dbSNP (ID: rs80359391), HGMD, and UMD (3X as a causal variant). The p.Cys1200X variant leads to a premature stop codon at position 1200, which is predicted to lead to 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 | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 15, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jun 06, 2023 | A known pathogenic variant was detected in the BRCA2 gene (p.Cys1200Ter). This sequence change creates a premature translational stop signal (p.Cys1200*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported in individuals with breast cancer, ovarian cancer, and Fanconi anemia (PMID: 24504028, 16683254, 25863477, 15645491, 24728189). This variant is also known as 3827delGT in the literature. ClinVar contains an entry for this variant (Variation ID: 51493) with 16 submissions, all pathogenic, 3 stars, no conflict, and reviewed by an expert panel. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic. - |
not provided Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 28, 2022 | Nonsense 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 BRCA2-related cancers (De Leon Matsuda et al., 2002; Liede et al., 2002; Song et al., 2014; Kang et al., 2015; Nielsen et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3827delGT; This variant is associated with the following publications: (PMID: 26833046, 32455662, 32980694, 31492746, 29922827, 34697415, 11920621, 12442265, 22798144, 24728189, 24504028, 26287763, 25863477, 26681312, 28166811, 27767231, 28617445, 29128982, 29348823, 29470806, 29446198, 30309222, 30287823, 30720243, 30702160, 30322717, 30972954, 31263054, 29176636, 33646313, 33372952, 33151324, 30787465, 31742824, 33087929, 34645131, 15645491) - |
| Pathogenic, criteria provided, single submitter | not provided | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Oct 21, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 16, 2020 | This frameshift variant causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in symptomatic individuals with breast and/or ovarian cancer and a boy with a phenotype of Fanconi Anemia in the published literature (PMIDs: 22798144 (2012), 24259538 (2014), 24728189 (2014), 26287763 (2015), 29348823 (2017), 30309222 (2019), and 30702160 (2019)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 30, 2017 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| 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 07, 2021 | Variant summary: BRCA2 c.3599_3600delGT (p.Cys1200X) 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 1.6e-05 in 254218 control chromosomes. c.3599_3600delGT has been widely 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. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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 | Dec 22, 2023 | This sequence change creates a premature translational stop signal (p.Cys1200*) 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 (rs80359391, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer, ovarian cancer, and Fanconi anemia (PMID: 15645491, 16683254, 24504028, 24728189, 25863477). This variant is also known as 3827delGT. ClinVar contains an entry for this variant (Variation ID: 51493). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.Cys1200X variant in BRCA2 (resulting from c.3599_3600delGT) has been reported in at least 13 individuals with BRCA2-related cancers (De Leon Matsuda 2002, Cunningham 2014, Susswein 2016, Hirasawa 2017, Momozawa 2018, BIC database). It has also been identified in 1/18394 East Asian 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 frameshift variant is predicted to lead to a premature termination codon at position 1200. 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 Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 51493). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 19, 2022 | The c.3599_3600delGT pathogenic mutation (also known as p.C1200*), located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at positions 3599 to 3600. This changes the amino acid from a cysteine to a stop codon within coding exon 10. This mutation has been reported in multiple individuals diagnosed with breast or ovarian cancer (De Leon Matsuda ML et al. Int. J. Cancer. 2002 Apr;98:596-603; Hamann U et al. Eur. J. Hum. Genet. 2003 Jun;11:464-7; Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Kang E et al. Breast Cancer Res Treat. 2015 May;151:157-68; Hirasawa A et al. Oncotarget. 2017 Dec;8:112258-112267; Kwon BS et al. Cancer Res Treat. 2018 Oct; Lovejoy LA et al. Austin J Cancer Clin Res. 2018 Jun; 5(1):1082; Bhaskaran SP et al. Int J Cancer. 2019 Jan). This mutation has also been reported in a child with biallelic BRCA2 related Fanconi Anemia who was diagnosed with leukemia by the age of 2 years (Meyer S et al. Genes Chromosomes Cancer. 2005 Apr;42:404-15). Of note, this alteration is also designated as 3827delGT 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 | Oct 25, 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 at least 10 individuals affected with breast and/or ovarian cancer (PMID: 11920621, 12774040, 20104584, 22798144, 24504028, 24728189, 26287763, 29348823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001069) and 2 individuals affected with prostate cancer (PMID: 31214711). This variant has been detected in a compound heterozygous carrier affected with Fanconi anemia (PMID: 15645491). This variant also has been detected in unaffected individuals (PMID: 11920621, 30287823, 31214711, 33471991; Leiden Open Variation Database DB-ID BRCA2_001069) and in 4/251042 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. - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
Chordoma Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Integrative Tumor Epidemiology Branch, National Institutes of Health | Mar 22, 2021 | - - |
BRCA2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 03, 2024 | The BRCA2 c.3599_3600delGT variant is predicted to result in premature protein termination (p.Cys1200*). This variant has been associated with breast cancer, ovarian cancer and severe Fanconi anemia (reported as 3827delGT in De Leon Matsuda et al. 2002. PubMed ID: 11920621; Arai et al. 2018. PubMed ID: 29176636; Hirasawa et al. 2017. PubMed ID: 29348823; Petridis et al. 2019. PubMed ID: 31263054; van der Hout et al. 2006. PubMed ID: 16683254; Meyer et al. 2005. PubMed ID: 15645491). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51493/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Rhabdomyosarcoma Pathogenic:1
| Pathogenic, no assertion criteria provided | provider interpretation | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Sep 01, 2020 | - - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 20, 2023 | - - |
Computational scores
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Details are displayed if max score is > 0.2
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