13-32379872-C-T
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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.9076C>T(p.Gln3026*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
NM_000059.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.31
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 13-32379872-C-T is Pathogenic according to our data. Variant chr13-32379872-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 38207.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32379872-C-T is described in Lovd as [Pathogenic]. Variant chr13-32379872-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.9076C>T | p.Gln3026* | stop_gained | 23/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.9076C>T | p.Gln3026* | stop_gained | 23/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.8707C>T | p.Gln2903* | stop_gained | 23/27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.*1134C>T | non_coding_transcript_exon_variant | 22/26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000614259.2 | n.*1134C>T | 3_prime_UTR_variant | 22/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461190Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726940
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1461190
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32
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1
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GnomAD4 genome
GnomAD4 genome
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32
Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:22
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 | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jan 29, 2013 | - - |
| 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 | Genomic Research Center, Shahid Beheshti University of Medical Sciences | Dec 03, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 08, 2014 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 18, 2018 | The p.Gln3026X variant in BRCA2 has been reported in >10 individuals with BRCA2- associated cancers (Ikeda 2001, Sekine 2001, Sugano 2008, Kang 2015, Arai 2018). It was also absent from large population studies. This nonsense variant leads t o a premature termination codon at position 3026, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene i s an established disease mechanism in hereditary breast and ovarian cancer (HBOC ). In addition, this variant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 38207). In summary, the p.Gln 3026X variant meets criteria to be classified as pathogenic for HBOC in an autos omal dominant manner. ACMG/AMP criteria applied: PVS1, PS4_Moderate, PM2. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 27, 2023 | ClinVar contains an entry for this variant (Variation ID: 38207). For these reasons, this variant has been classified as Pathogenic. RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11595708, 19016756, 22632462, 25863477, 26187060, 27732944, 28008555, 28205045). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln3026*) 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). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Apr 18, 2017 | - - |
| Pathogenic, criteria provided, single submitter | research | Research Institute, Aichi Cancer Center | Feb 01, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 07, 2019 | Variant summary: BRCA2 c.9076C>T (p.Gln3026X) 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 (e.g. c.9093_9094delinsG/p.Thr3033fsX29, c.9097dupA/p.Thr3033fsX11). The variant was absent in 246292 control chromosomes (gnomAD). c.9076C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Malone_2006, Kang_2015, Palmero_2018). These data indicate that the variant is very likely to be associated with disease. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.6237_6238delGT, p.Leu2080ArgfsX4) possibly in a patient with Fanconi Anemia (BRCA Share database). One study showed this variant did not significantly affect splicing (Acedo_2012). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2024 | 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; 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 9304C>T; This variant is associated with the following publications: (PMID: 22798144, 11149425, 33309985, 33057194, 36243179, 35982159, 28440963, 32980694, 32826389, 19016756, 25863477, 23893897, 26187060, 11595708, 28008555, 28205045, 27732944, 29439820, 30287823, 28111427, 29446198, 25525159, 31447099, 32710294, 30787465, 35741847, 31723001, 34645131, 29176636, 30350268, 22632462) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 15, 2024 | The BRCA2 c.9076C>T (p.Gln3026*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 35741847 (2022), 34645131 (2022), 33471991 (2021), 32710294 (2021), 29907814 (2018), 29176636 (2018), 28205045 (2017), 25863477 (2015), 22798144 (2012), 19016756 (2008), 11595708 (2001)), including triple negative breast cancer (PMID: 30350268 (2018)) and male breast cancer (PMIDs: 30287823 (2018), 28008555 (2017)). Additionally, this variant has been reported in individuals with prostate cancer (PMID: 29439820 (2018)) and pancreatic cancer (PMID: 27732944 (2016)). Experimental studies show conflicting evidence of this variant's impact on splicing (PMIDs: 25525159 (2015), 22632462 (2012)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 31, 2017 | The BRCA2 c.9076C>T, p.Gln3026Ter variant (rs80359159) has been reported in a family with breast and ovarian cancer (Sekine 2001). Minigene analysis indicates that the variant generates a transcript that leads to a premature termination codon through a frameshift or nonsense codon, or a transcript lacking 2 exons and approximately 101 amino acids (Acedo 2012). The variant is classified as pathogenic in ClinVar (Variation ID: 38207), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Acedo A et al. Comprehensive splicing functional analysis of DNA variants of the BRCA2 gene by hybrid minigenes. Breast Cancer Res. 2012; 14(3):R87. Sekine M et al. Mutational analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families: two common founder mutations of BRCA1 in Japanese population. Clin Cancer Res. 2001; 7(10):3144-50. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 06, 2022 | The p.Q3026* pathogenic mutation (also known as c.9076C>T), located in coding exon 22 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9076. This changes the amino acid from a glutamine to a stop codon within coding exon 22. This mutation has been identified in multiple hereditary breast and/or ovarian cancer families (Sekine M et al. Clin Cancer Res. 2001 Oct;7(10):3144-50; Arai M et al. J. Hum. Genet. 2018 Apr;63(4):447-457; Momozowa Y et al. Nat Commun 2018 10;9(1):4083). Of note, this mutation is also designated as 9304C>T 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 | Jan 04, 2022 | This variant changes 1 nucleotide in exon 23 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A minigene splicing assay has shown partial splicing defect (PMID: 22632462). This variant has been reported in at least a dozen individuals affected with breast or ovarian cancer (PMID: 11149425, 19016756, 22798144, 28008555, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001520), in families suspected of being affected with hereditary breast and ovarian cancer (PMID: 11595708, 25863477) and in individuals affected with pancreatic or prostate cancer (PMID: 27732944, 31214711, 32980694). 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. - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jul 30, 2014 | - - |
BRCA2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 28, 2024 | The BRCA2 c.9076C>T variant is predicted to result in premature protein termination (p.Gln3026*). This variant was reported in multiple individuals with breast, ovarian cancer, or other cancers (see examples: Table 2, Sekine et al. 2001. PubMed ID: 11595708; Momozawa et al. 2018. PubMed ID: 30287823; Figure 1 and Table S1, Park. 2017. PubMed ID: 28111427; Table 1, Antonarakis. 2018. PubMed ID: 29439820). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/38207/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Gln3026X variant has been reported in 4 of 4712 proband chromosomes from individuals with breast or ovarian cancer (Sekine 2001, Sugano 2008, Kim 2012). This variant leads to a premature stop codon at position 3026, 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 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. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 14, 2024 | - - |
Computational scores
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Name
Calibrated prediction
Score
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at