rs80358533
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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.2830A>T(p.Lys944Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,668 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: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 stop_gained
NM_000059.4 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: -0.0630
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 13-32337185-A-T is Pathogenic according to our data. Variant chr13-32337185-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 51355.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337185-A-T is described in Lovd as [Pathogenic]. Variant chr13-32337185-A-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.2830A>T | p.Lys944Ter | stop_gained | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.2830A>T | p.Lys944Ter | stop_gained | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250612Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135612
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461430Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2AN XY: 727002
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GnomAD4 genome 0.00000657 AC: 1AN: 152238Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74376
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:38
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:12
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 11, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | New York Genome Center | Mar 10, 2020 | The c.2830A>T (p.Lys944Ter) variant identified in the BRCA2 gene of this individual leads to the premature termination of the protein at amino acid 944/3419 (coding exon 11/27). This variant is found with low frequency in gnomAD (3 heterozygotes, 0 homozygotes, allele frequency: 1.06e-5) suggesting it is not a common benign variant in the populations represented in these databases. This variant is reported as Pathogenic in ClinVar (VarID:51355) after review by the Expert Panel and has been reported in many affected individuals in the literature [PMID: 24737347; PMID: 23683081; PMID: 20104584; PMID: 28346442]. It is reported here as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Pathogenic, no assertion criteria provided | case-control | Molecular Oncology, Hospital Universitario Central de Asturias (HUCA) | May 24, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 01, 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 | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Nov 27, 2006 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not provided Pathogenic:9
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 30, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 26, 2019 | This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in a number of individuals with breast and ovarian cancers (PMID: 27767231 (2017), 26681312 (2015), 23940062 (2013), 23683081 (2013), 20104584 (2010), 16760289 (2006), 9150154 (1997)) and in one case of pancreatic cancer (PMID: 29506128 (2018)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Clinical Genetics and Genomic Diagnostics, Zealand University Hospital | May 01, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 06, 2021 | 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; Not observed at a significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 25525159, 26659639, 20104584, 23683081, 26064523, 25428789, 9150154, 16760289, 23940062, 22535016, 11430722, 20608899, 10359546, 16847550, 14732925, 24737347, 9892109, 18465347, 11710835, 27767231, 27836010, 28127413, 26681312, 29339979, 28993434, 29506128, 29446198, 30720243, 30702160, 30322717, 31589614, 32885271, 33087929, 33287145) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Nov 07, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 15, 2024 | PM3, PM5_strong, PVS1 - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jun 20, 2023 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 14, 2019 | The p.Lys944X variant in BRCA2 has been reported in at least 11 individuals with BRCA2-related cancers; however two of these individuals harbored pathogenic variants in BRCA1 as well (Hakansson 1997, Heidemann 2012, Vietri 2013, Susswein 2016, Weren 2017, Lowery 2018, Wen 2018, BIC database). In addition, this variant was reported in one proband with Fanconi anemia who was compound heterozygous for this variant and a second variant in BRCA2 (Bodd 2010). The p.Lys944X variant has also been identified in 0.004% (1/24868) of African 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 nonsense variant is predicted to lead to a premature termination codon at position 944. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. Additionally, this variant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 51355). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PP1. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| 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 | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Jan 30, 2019 | The c.2830A>T (p.Lys944*) variant of BRCA2 results in an early stop codon at amino acid 944, resulting in an absent or disrupted protein product. Loss of function variants of BRCA2 are known to be pathogenic. The variant has been reported in several individuals and families with breast and/or ovarian cancer and pancreatic cancer (PMID: 29506128, 29446198, 29339979, 28346442, 27836010, 27767231, 26681312, 24737347, 23940062, 23683081, 22535016, 20104584, 18465347, 16760289, 10359546 and 9150154). This variant is observed in the population database at very low frequency (3/282020). Based on the currently available information, the c.2830A>T (p.Lys944*) variant of BRCA2 is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 30, 2021 | Variant summary: BRCA2 c.2830A>T (p.Lys944X) 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 8e-06 in 250612 control chromosomes. c.2830A>T 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 12, 2024 | This sequence change creates a premature translational stop signal (p.Lys944*) 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 (rs80358533, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150154, 20104584, 23683081, 26681312, 27836010). This variant is also known as 3058A>T. ClinVar contains an entry for this variant (Variation ID: 51355). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | research | Research Institute, Aichi Cancer Center | Feb 01, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 20, 2023 | This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals with a personal and/or family history of breast, ovarian, or pancreatic cancer (PMID: 18465347, 18284688, 19574032, 20104584, 22535016, 23096105, 23683081, 29446198, 30322717, 32885271, 34072659. 34309133). This variant has been identified in 3/282020 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 | Oct 01, 2021 | The p.K944* pathogenic mutation (also known as c.2830A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 2830. This changes the amino acid from a lysine to a stop codon within coding exon 10. This mutation has been detected in multiple breast and ovarian cancer families to date (Mote PA et al. Genes Chromosomes Cancer, 2004 Mar;39:236-48; Capalbo C et al. Ann Oncol, 2006 Jun;17 Suppl 7:vii34-40; Thomassen M et al. Acta Oncol, 2008;47:772-7; Bodd TL et al. Acta Paediatr., 2010 Nov;99:1741-3; Heidemann S et al. Breast Cancer Res Treat, 2012 Aug;134:1229-39; Vietri MT et al. Clin. Chem. Lab. Med., 2013 Dec;51:2319-24; Lucas AL et al. Cancer, 2014 Jul;120:1960-7; Rebbeck TR et al. Breast Cancer Res, 2016 11;18:112; Susswein LR et al. Genet Med, 2016 08;18:823-32; Weren RD et al. Hum. Mutat., 2017 02;38:226-235; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Wen WX et al. J Med Genet, 2018 02;55:97-103; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Chen B et al. Aging (Albany NY), 2020 02;12:3140-3155; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In one study, this variant was reported in 2/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been reported in patients with pancreatic cancer (Lowery MA et al. J Natl Cancer Inst, 2018 10;110:1067-1074; Sorscher S et al. Oncologist, 2021 Jul). Of note, this alteration is also designated as 3058A>T in the 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 | Jun 19, 2021 | - - |
BRCA2-related cancer predisposition Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jul 29, 2024 | This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals with a personal and/or family history of breast, ovarian, or pancreatic cancer (PMID: 18465347, 18284688, 19574032, 20104584, 22535016, 23096105, 23683081, 29446198, 30322717, 32885271, 34072659. 34309133). This variant has been identified in 3/282020 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. - |
Fanconi anemia complementation group D1 Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Feb 05, 2020 | - - |
BRCA2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 20, 2024 | The BRCA2 c.2830A>T variant is predicted to result in premature protein termination (p.Lys944*). This variant has been reported in multiple individuals with breast and/or ovarian cancer (Table 2, Hakansson et al. 1997. PubMed ID: 9150154; Figure 1, Heidemann et al. 2012. PubMed ID: 22535016; Table 1, Weren et al. 2016. PubMed ID: 27767231). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD and it has been classified as pathogenic by an expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51355/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Medulloblastoma;C0346153:Familial cancer of breast;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C2931456:Familial prostate cancer;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PVS1+PS4_Moderate - |
Malignant tumor of breast Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Lys944X variant was identified in 8 of 25752 proband chromosomes (frequency: 0.0003) from individuals or families with breast and ovarian cancer (Blay 2013, Borg 2010, Capalbo 2006, Hakansson 1997, Heramb 2018, Susswein 2015). The variant was also identified in the following databases: dbSNP (ID: rs80358533) as "With Pathogenic allele", ClinVar (12x pathogenic), Clinvitae (5x pathogenic), GeneInsight-COGR (2x pathogenic), Cosmic (1x, confirmed somatic, in carcinoma of the biliary tract), LOVD 3.0 (11x), UMD-LSDB (8x causal), BIC Database (6x pathogenic), and ARUP Laboratories (pathogenic). The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 3 of 276604 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 23994 chromosomes (freq: 0.00004), European in 1 of 126388 chromosomes (freq: 0.000008), and South Asian in 1 of 30678 chromosomes (freq: 0.00003). The variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The c.2830A>T variant leads to a premature stop codon at position 944 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. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Ovarian neoplasm Pathogenic:1
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Computational scores
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D
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N
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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