rs28897756
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PP4_Strong
This summary comes from the ClinGen Evidence Repository: The c.9117G>A variant in BRCA2 is a synonymous variant (p.Pro3039=). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by exon skipping (PMIDs: 17011978, 23451180, 22505045, 31843900, 32398771, 22632462). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3364.725 (based on Co-occurrence LR=2.231; Family History LR=1508.137), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very Strong met; PMID:17924331, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_VeryStrong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA025994/MONDO:0012933/097
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 splice_region, synonymous
NM_000059.4 splice_region, synonymous
Scores
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.22
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 12 ACMG points.
PVS1
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.9117G>A | p.Pro3039= | splice_region_variant, synonymous_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.9117G>A | p.Pro3039= | splice_region_variant, synonymous_variant | 23/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152108Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248378Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134406
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:36
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:14
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Aug 31, 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, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 03, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Nov 02, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | May 25, 2017 | The c.9117G>A (p.Pro3039Pro) variant in the BRCA2 gene has been detected in multiple patients and families with breast and/or ovarian cancer [PMID 10638982 reported as 3398delAAAAG, 27000661] and a cohort of patients with prostate cancer [PMID 23035815, reported as c.9117 G>A (p.Val2985fs)]. The nucleotide position 9117 is the last nucleotide of exon 23. Several in vitro assays showed that the change leads aberrant splicing and the skipping of exon 23 [PMID 22505045, 23451180]. This variant is thus predicted to result in a loss of function of the protein. This variant has not been reported in the ExAC database. This variant thus classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 18, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 09, 2023 | This variant changes a conserved and the last nucleotide in exon 23, and it is predicted to disrupt the intron 23 splice donor site. RNA studies have shown that this variant impacts splicing resulting in exon 23 skipping and introducing premature stop (PMID: 22505045, 23451180, 25382762, 27060066, 31843900, 32393398). 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 or ovarian cancer (PMID: 18821011, 22798144, 24156927, 24249303, 25480878, 25556971, 25948282, 26026974, 27000661, 28477318, 28724667, 30287823). This variant has been identified in 1/248378 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 | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 10, 2014 | - - |
not provided Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 06, 2019 | It has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 10638982 (2000), 17011978 (2006), 17924331 (2007), 22505045 (2012), 21990134 (2012), 23451180 (2013), 28724667 (2017)). Furthermore, experimental studies have shown that the variant causes the skipping of exon 23, resulting in premature termination in protein synthesis (PMID: 22505045 (2012), 22632462 (2012), 23451180 (2013), and 27060066 (2016)). Based on the available information, the variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 17, 2024 | Alters the last nucleotide of the exon and has been demonstrated to cause aberrant splicing, predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 10638982, 17011978, 22632462, 23451180, 25382762); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (PMID: 17924331, 21990134); Published functional studies demonstrate a damaging effect: reduced homology-directed repair (HDR) activity (PMID: 32398771); Observed in multiple breast/ovarian cancer families (PMID: 10638982, 17148771, 22923021, 24156927, 26026974, 28477318, 28724667); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9345G>A; This variant is associated with the following publications: (PMID: 22798144, 17011978, 22505045, 22632462, 26026974, 25948282, 33309985, 36367610, 35142179, 36881271, 36243179, 34887416, 36113475, 37310942, 35864222, 28477318, 29084914, 34413315, 38075165, 29922827, 28888541, 31447099, 32658311, 17924331, 23451180, 23035815, 22923021, 17148771, 20507642, 22217648, 18375895, 10638982, 9133456, 21324516, 18821011, 25556971, 28008555, 24156927, 27000661, 21702907, 28740454, 28873162, 27271530, 25186627, 28724667, 29805665, 29907814, 29339979, 28825054, 30702160, 31957001, 31143373, 29176636, 31825140, 31892343, 31723001, 35273153, 34645131, 33804961, 34808016, 32338768, 32393398, 32853339, 30787465, 36988593, 36000185, 25382762, 21990134, 32398771) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 26, 2022 | - - |
| 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 | Clinical Genetics and Genomics, Karolinska University Hospital | Nov 03, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change affects codon 3039 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. 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 variant has been observed in individual(s) with breast, ovarian, or prostate cancer (PMID: 10638982, 17011978, 17148771, 22923021, 23035815, 26026974). This variant is also known as 9345G>A. ClinVar contains an entry for this variant (Variation ID: 38215). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 23 and introduces a premature termination codon (PMID: 22505045, 22632462, 23035815, 23451180, 25382762; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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 | Oct 08, 2020 | Variant summary: BRCA2 c.9117G>A (p.Pro3039Pro) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict that the variant abolishes a 5' splicing donor site. Multiple publications report experimental evidence that this variant affects mRNA splicing (e.g. Bonatti_2006, Acedo_2012, Houdayer_2012, Colombo_2013). The variant allele was found at a frequency of 4e-06 in 248378 control chromosomes. c.9117G>A has been reported in the literature in many individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Peelen_2000, Meindl_2002, Bonatti_2006, Novakovic_2012, Nakamura_2013, Corman_2016, Barrios_2017). These data indicate that the variant is very likely to be associated with disease. 17 other ClinVar submitters, including an expert panel (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2022 | The p.Pro3039Pro (c.9117G>A) variant in BRCA2 has been reported in at least 16 individuals with BRCA2-related cancer (Peelen 2000 PMID: 10638982, Houdayer 2012 PMID: 22505045, Willems-Jones 2012 PMID: 23035815, de Juan 2015 PMID: 26026974, Corman 2016 PMID: 27000661, Labidi-Galy 2018 PMID: 29084914). It has also been identified in 1/111660 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 has also been identified in ClinVar (Variation ID: 38215). This variant is located in the last base of the exon, which is part of the 5’ splice region. Computational tools predict a splicing impact, and both in vitro studies and testing of patient RNA have shown that this variant results in exon skipping, which is predicted to lead to an absent or truncated protein (Peelen 2000 PMID: 10638982, Acedo 2012 PMID: 22632462, Houdayer 2012 PMID: 22505045, Colombo 2013 PMID: 23451180). Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Another variant, c.9117G>T, resulting in the same synonymous change and predicted splicing impact has also been identified in individuals with BRCA2-related cancers. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS3, PM2, PS4. - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 08, 2022 | The c.9117G>A pathogenic mutation (also known as p.P3039P), located in coding exon 22 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9117. This nucleotide substitution does not change the at codon 3039. However, this change occurs in the last base pair of coding exon 22 and has been shown to cause aberrant RNA transcripts due to exon skipping that results in a frameshift at codon 2985 and premature protein truncation (V2985Gfs*3) (Ambry internal data; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Acedo A et al. Hum. Mutat. 2015 Feb;36:210-21). This alteration has been reported in multiple families with hereditary breast and/or ovarian cancer (Hamann U et al. J. Med. Genet. 2002 Mar;39:E12; Spurdle AB et al. J. Clin. Oncol. 2008 Apr;26:1657-63; Fong PC et al. J. Clin. Oncol. 2010 May;28:2512-9; Novakovi S et al. Int. J. Oncol. 2012 Nov;41:1619-27; Takahashi M et al. Breast Cancer. 2017 Mar;24(2):336-340; Heramb C et al. Hered Cancer Clin Pract 2018 Jan;16:3; Arai M et al. J. Hum. Genet. 2018 Apr;63(4):447-457). This alteration has also been reported in a male with aggressive prostate cancer (Willems-Jones A et al. BJU Int. 2012 Dec;110:E1181-6) and in biological males with breast cancer (de Juan I et al. Fam. Cancer. 2015 Dec;14:505-13; Corman V et al. Endocr. Relat. Cancer. 2016 May;23:391-7). Of note, this mutation is also designated as 9345G>A in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 19, 2023 | This variant changes a conserved and the last nucleotide in exon 23, and it is predicted to disrupt the intron 23 splice donor site. RNA studies have shown that this variant impacts splicing resulting in exon 23 skipping and introducing premature stop (PMID: 22505045, 23451180, 25382762, 27060066, 31843900, 32393398). 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 or ovarian cancer (PMID: 18821011, 22798144, 24156927, 24249303, 25480878, 25556971, 25948282, 26026974, 27000661, 28477318, 28724667, 30287823). This variant has been identified in 1/248378 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. - |
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 | Oct 31, 2018 | - - |
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 | - - |
Hereditary breast ovarian cancer syndrome;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1
| Pathogenic, no assertion criteria provided | research | King Laboratory, University of Washington | Sep 01, 2019 | - - |
Medulloblastoma;C0040588:Tracheoesophageal fistula;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 18, 2017 | - - |
BRCA2-related cancer predisposition Pathogenic:1
| Pathogenic, reviewed by expert panel | curation | ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen | Jun 11, 2024 | The c.9117G>A variant in BRCA2 is a synonymous variant (p.Pro3039=). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by exon skipping (PMIDs: 17011978, 23451180, 22505045, 31843900, 32398771, 22632462). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3364.725 (based on Co-occurrence LR=2.231; Family History LR=1508.137), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very Strong met; PMID: 17924331, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_VeryStrong). - |
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 | Jan 31, 2024 | - - |
Breast carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 09, 2021 | Diagnosis: Breast cancer Pathology: Invasive ductal breast carcinoma IHC: ER:+, PR:+, HER2:- - |
Computational scores
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SpliceAI score (max)
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at