rs80358474
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.1832C>A(p.Ser611Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S611S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
BRCA2
NM_000059.4 stop_gained
NM_000059.4 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: 0.169
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 13-32333310-C-A is Pathogenic according to our data. Variant chr13-32333310-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 37764.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32333310-C-A is described in Lovd as [Pathogenic]. Variant chr13-32333310-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.1832C>A | p.Ser611Ter | stop_gained | 10/27 | ENST00000380152.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.1832C>A | p.Ser611Ter | stop_gained | 10/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
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 | 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, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Dec 22, 2011 | - - |
| 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, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 08, 2023 | This variant changes 1 nucleotide in exon 10 of the BRCA2 gene, creating a 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 six individuals affected with breast cancer (PMID: 21614564, 25151137, 26681312, 33471991; Leiden Open Variation Database DB-ID BRCA2_004282; Color internal data) and in suspected hereditary breast and ovarian cancer families (PMID: 15131399, 24156927). 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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 04, 2016 | Variant summary: The BRCA2 c.1832C>A (p.Ser611X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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.1842dupT (p.Asn615X) and c.1855C>T (p.Gln619X). The variant of interest was not found in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals. In addition, multiple reputable databases/clinical laboratories classify the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Apr 10, 2021 | The c.1832C>A (p.Ser611*) variant in the BRCA2 gene is located on the exon 10 and introduces a premature translation termination codon (p.Ser611*), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast and/or ovarian cancer (PMID: 26848529, 26552643, 15131399, 26681312). Loss-of-function variants in BRCA2 gene are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 37764) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.1832C>A (p.Ser611*) variant in the BRCA2 gene has been classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Variantyx, Inc. | Nov 07, 2022 | This is a nonsense variant in the BRCA2 gene (OMIM 600185). Heterozygous pathogenic variants in this gene have been associated with autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). This variant introduces a premature termination codon in exon 10 out of 27. It is expected to result in loss of function, which is a known disease mechanism for BRCA2 (PMID: 20301425) (PVS1). Multiple reputable laboratories have reported this variant as pathogenic or likely pathogenic, and this classification has been supported by an expert panel in ClinVar (PP5). This variant is absent from control populations (https://gnomad.broadinstitute.org/) (PM2_Supporting). Based on the current evidence, this variant is classified as pathogenic for autosomal dominant HBOC. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change creates a premature translational stop signal (p.Ser611*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 15131399, 24156927, 26187060, 26681312, 26848529). This variant is also known as 2060C>A. ClinVar contains an entry for this variant (Variation ID: 37764). 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, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 13, 2017 | The BRCA2 c.1832C>A; p.Ser611Ter variant (rs80358474), also known as 2060C>A, has previously been associated with hereditary breast and ovarian cancer syndrome (Kwong 2016, Lubinski 2004, Susswein 2016). This variant is reported multiple times in the ClinVar database as pathogenic (Variation ID: 37764), and is observed in general population databases at a low frequency of 0.001 percent (3/236032 alleles, Genome Aggregation Database). This variant induces an early termination codon and is predicted to result in a truncated protein or absent transcript. Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Ser611Ter: https://www.ncbi.nlm.nih.gov/clinvar/variation/37764/ Kwong A et al. Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries. J Med Genet. 2016 Jan;53(1):15-23. Lubinski J et al. Cancer variation associated with the position of the mutation in the BRCA2 gene. Fam Cancer. 2004;3(1):1-10. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 09, 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 in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2060C>A; This variant is associated with the following publications: (PMID: 25085752, 26552643, 21614564, 15131399, 25525159, 26681312, 26187060, 26848529, 25151137, 28918466, 29446198, 30702160, 32341426, 31825140, 30787465) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 16, 2022 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. In the published literature, this variant has been reported in individuals with breast and ovarian cancer in the published literature (PMID: 31825140 (2019), 30702160 (2019), 29446198 (2018), 26848529 (2016), 26681312 (2015), 26552643 (2015), 26187060 (2015), 23318652 (2013), 21614564 (2012), 15131399 (2004)). 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 17, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 18, 2023 | This variant changes 1 nucleotide in exon 10 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 detected in at least six individuals affected with breast cancer (PMID: 21614564, 25151137, 26681312, 33471991; Leiden Open Variation Database DB-ID BRCA2_004282; Color internal data) and in suspected hereditary breast and ovarian cancer families (PMID: 15131399, 24156927). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 02, 2021 | The p.S611* pathogenic mutation (also known as c.1832C>A), located in coding exon 9 of the BRCA2 gene, results from a C to A substitution at nucleotide position 1832. This changes the amino acid from a serine to a stop codon within coding exon 9. This alteration was classified as pathogenic by a statistical variant reclassification tool based on probands' clinical histories (Pruss D et al. Breast Cancer Res Treat, 2014 Aug;147:119-32). This mutation (also designated 2060C>A) has been reported in multiple hereditary breast and ovarian cancer families (Lubinski J et al. Fam. Cancer. 2004;3:1-10; Cao W et al. J. Epidemiol. 2013;23:75-84; Zhang J et al. Breast Cancer Res Treat, 2012 Apr;132:421-8). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 08;18:823-32). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). 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. - |
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.Ser611X variant was identified in 1 of 880 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Lubinski 2004). The variant was also identified in dbSNP (ID: rs80358474) “With Pathogenic allele”, HGMD, LOVD, the BIC database (14X with clinical importance; classified as pathogenic), the ClinVar database (classified pathogenic by Ambry Genetics, and by the Sharing Clinical Reports Project (derived from Myriad reports)). The p.Ser611X variant leads to a premature stop codon at position 611, 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 | Jan 26, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at