13-32340392-A-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.6037A>T(p.Lys2013Ter) 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 (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
BRCA2
NM_000059.4 stop_gained
NM_000059.4 stop_gained
Scores
2
5
Clinical Significance
Conservation
PhyloP100: 0.484
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 13-32340392-A-T is Pathogenic according to our data. Variant chr13-32340392-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 38016.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340392-A-T is described in Lovd as [Pathogenic]. Variant chr13-32340392-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.6037A>T | p.Lys2013Ter | 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.6037A>T | p.Lys2013Ter | stop_gained | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 44
GnomAD4 exome
Cov.:
44
GnomAD4 genome
GnomAD4 genome
Cov.:
33
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:21
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7
| Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Jun 17, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Feb 23, 2018 | This c.6037A>T (p.Lys2013*), variant in exon 11 of the BRCA2 gene creates a stop codon which is predicted to lead to nonsense-mediated mRNA decay, which is a known disease mechanism for this gene. This variant has been reported in multiple hereditary breast and ovarian cancer patients (PMID: 17513806, 21913181, 22006311, 23961350, 24504028, 25111659). Therefore, the c.6037A>T (p.Lys2013*) variant in the BRCA2 gene is classified as pathogenic. - |
| 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) | May 29, 2002 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 11802209, 11897832, 16168123, 17513806, 21913181, 22006311, 23961350, 24504028, 24728189, 25111659, 24728189, 29084914, 29360161, 32380732, 32438681), pancreatic cancer (PMID: 29360161), or prostate cancer (PMID: 25111659). 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, 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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:6
| 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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 13, 2023 | Variant summary: BRCA2 c.6037A>T (p.Lys2013X) results in a premature termination codon, predicted to cause an absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 253864 control chromosomes. c.6037A>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Meindl_2002, Machado_2007, Song_2014, Litton_2011, Tarabeux_2014, Solano_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 11802209, 23961350, 21913181, 23942203, 17513806, 24728189, Solano et al.,(2016) Oncotarget). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic, including 1 expert panel (ENIGMA). 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 24, 2024 | This sequence change creates a premature translational stop signal (p.Lys2013*) 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 cancer, ovarian cancer, fallopian tube cancer, and prostate cancer (PMID: 11802209, 11897832, 17513806, 22006311, 24504028, 24728189, 25111659). This variant is also known as 6265A>T. ClinVar contains an entry for this variant (Variation ID: 38016). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This variant is a single amino acid change from Lysine to a Termination codon at amino acid residue 2013 of the BRCA2 gene. It is expected to result in a truncated, non-functional protein. Truncating variants in the BRCA2 gene are known to be pathogenic. This variant is also known as 6265A>T in the literature and has been reported in patients with breast, ovarian, fallopian tube and prostate cancer (PMID: 11802209, 11897832, 22006311, 25111659). The mutation database ClinVar contains entries for this variant (Variation ID: 38016). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 30, 2015 | The p.Lys2013X variant has been reported in >20 individuals with BRCA2-associate d cancers (Meindl 2002, Hamann 2002, Wappenschmidt 2005, Machado 2007, Walsh 201 1, Litton 2012, Solano 2012, Cunningham 2014, Maier 2014, Breast Cancer Informat ion Core (BIC) database). It was absent from large control studies. This nonsens e variant leads to a premature termination codon at position 2013, which is pred icted to lead to a truncated or absent protein. Heterozygous loss of BRCA2 funct ion is an established disease mechanism in hereditary breast and ovarian cancer (HBOC). In summary, this variant meets criteria to be classified as pathogenic f or HBOC in an autosomal dominant manner based upon the predicted impact to the p rotein and presence in affected individuals. - |
not provided Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 03, 2019 | This nonsense variant causes the premature termination of BRCA2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in cases of breast, ovarian, prostate, and fallopian tube cancer, and described as deleterious in the published literature (PMID: 24728189 (2014), 25111659 (2014), 21913181 (2012), 22006311 (2011), 11897832 (2002), 11802209 (2002)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 02, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 06, 2023 | 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 significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 6265A>T; This variant is associated with the following publications: (PMID: 22006311, 24784157, 21913181, 32438681, 29922827, 24504028, 25896959, 11802209, 25111659, 25525159, 24728189, 27225637, 19941162, 16168123, 28127413, 23961350, 28259476, 11897832, 17513806, 27463008, 25085752, 29360161, 29084914, 30128899, 26556299, 30487452, 29061375, 29446198, 29625052, 26689913, 31447099, 31514334, 30787465, 35264596, 31892343) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 28, 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 affected with breast or ovarian cancer (PMID: 11802209, 11897832, 16168123, 17513806, 21913181, 22006311, 23961350, 24504028, 24728189, 25111659, 24728189, 29084914, 29360161, 32380732, 32438681), pancreatic cancer (PMID: 29360161), or prostate cancer (PMID: 25111659). 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 | Mar 08, 2022 | The p.K2013* pathogenic mutation (also known as c.6037A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 6037. This changes the amino acid from a lysine to a stop codon within coding exon 10. This mutation has been described in multiple breast, ovarian, pancreatic, and prostate cancer patients and families (Meindl A et al. Int. J. Cancer. 2002 Feb;97:472-80; Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026; Maier C et al. Prostate. 2014 Oct;74:1444-51; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24:326-333; Dudley B et al. Cancer. 2018 Apr;124:1691-1700). Of note, this alteration is also designated as 6265A>T in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 04, 2016 | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 13, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Benign
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
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