13-32379885-CAAAA-CAAA
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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.9097del(p.Thr3033LeufsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T3030T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.820
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 13-32379885-CA-C is Pathogenic according to our data. Variant chr13-32379885-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 38209.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379885-CA-C is described in Lovd as [Pathogenic]. Variant chr13-32379885-CA-C is described in Lovd as [Pathogenic]. Variant chr13-32379885-CA-C is described in Lovd as [Pathogenic]. Variant chr13-32379885-CA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.9097del | p.Thr3033LeufsTer29 | frameshift_variant | 23/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.9097del | p.Thr3033LeufsTer29 | frameshift_variant | 23/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461070Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 726802
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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1461070
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32
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726802
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:19
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| 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 | Counsyl | Oct 10, 2016 | - - |
| Pathogenic, criteria provided, single submitter | not provided | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | - | - - |
not provided Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 02, 2020 | This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 28993434 (2018), 16683254 (2006)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 17, 2018 | This deletion of one nucleotide in BRCA2 is denoted c.9097delA at the cDNA level and p.Thr3033LeufsX29 (T3033LfsX29) at the protein level. Using alternate nomenclature, this variant would also be defined as BRCA2 9090delA or BRCA2 9325delA. The normal sequence, with the base that is deleted in brackets, is CAAAAAAA[delA]CTCA. The deletion causes a frameshift which changes a Threonine to a Leucine at codon 3033, and creates a premature stop codon at position 29 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.9097delA has been observed in numerous breast and/or ovarian cancer probands and families (van der Hout 2006, Caux-Moncoutier 2011, Miolo 2009, Ang 2007, Kang 2014, Peixoto 2014, Wong 2015). We consider this variant to be pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 23, 2022 | The c.9097delA pathogenic mutation, located in coding exon 22 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 9097, causing a translational frameshift with a predicted alternate stop codon (p.T3033Lfs*29). This mutation has been reported in multiple individuals with hereditary breast and/or ovarian cancer (van der Hout AH et al. Hum. Mutat., 2006 Jul;27:654-66; Kang E et al. Breast Cancer Res. Treat., 2015 May;151:157-68; Caux-Moncoutier V et al. Hum. Mutat. 2011 Mar;32(3):325-34). 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 | Nov 15, 2021 | This variant deletes 1 nucleotide in exon 23 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. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least five individuals affected with breast cancer or breast and ovarian cancer (PMID: 18006916, 19818148, 26221963, 28993434; Color internal data). This variant has not been identified 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. - |
Familial cancer of breast Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 02, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 25, 2024 | Criteria applied: PVS1,PM5_STR - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 18, 2023 | This sequence change creates a premature translational stop signal (p.Thr3033Leufs*29) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 16683254, 21120943, 24578186, 24916970, 25863477, 26187060). ClinVar contains an entry for this variant (Variation ID: 38209). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 21, 2022 | Variant summary: BRCA2 c.9097delA (p.Thr3033LeufsX29) 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 1.2e-05 in 245952 control chromosomes. c.9097delA has been reported in the literature in numerous individuals affected with Hereditary Breast And Ovarian Cancer Syndrome. 11 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. - |
BRCA2-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 23, 2023 | The BRCA2 c.9097delA variant is predicted to result in a frameshift and premature protein termination (p.Thr3033Leufs*29). This variant has been reported in several individuals with breast cancer (van der Hout et al 2006. PubMed ID: 16683254; Santonocito C et al 2020. PubMed ID: 32438681) and it is classified as pathogenic by over ten submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38209/). This variant is documented in 0.0056% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32954022-CA-C). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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