chr13-32332770-CAG-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.1296_1297del(p.Asn433GlnfsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T431T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.413
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]
Genome browser will be placed here
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 13-32332770-CAG-C is Pathogenic according to our data. Variant chr13-32332770-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 37736.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332770-CAG-C is described in Lovd as [Pathogenic]. Variant chr13-32332770-CAG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.1296_1297del | p.Asn433GlnfsTer18 | frameshift_variant | 10/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.1296_1297del | p.Asn433GlnfsTer18 | frameshift_variant | 10/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
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:10
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 12, 2021 | - - |
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 | Sharing Clinical Reports Project (SCRP) | Oct 18, 2010 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 21, 2015 | - - |
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 Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
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, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2023 | BRCA2: PVS1, PM2, PS4:Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 17, 2023 | The BRCA2 c.1296_1297del (p.Asn433Glnfs*18) variant alters the translational reading frame of the BRCA2 mRNA and 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: 32393398 (2020), 32438681 (2020), 25682074 (2015)). 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 | GeneDx | May 09, 2023 | Frameshift 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; Observed in individuals with breast and/or ovarian cancer (Wong-Brown et al., 2015; Pritzlaff et al., 2016; Lang et al., 2017; Meisel et al., 2017; Arai et al., 2018; Carter et al., 2018); Also known as 1524_1525delGA; This variant is associated with the following publications: (PMID: 28008555, 28324225, 32438681, 25682074, 25980754, 29339979, 31825140, 32318955, 29176636, 30787465, 28294317, 30322717, 30702160, 32393398) - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 30, 2023 | This sequence change creates a premature translational stop signal (p.Asn433Glnfs*18) 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 a history of Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25682074, 25980754, 28008555). This variant is also known as 1524delGA. ClinVar contains an entry for this variant (Variation ID: 37736). 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 | Jul 11, 2018 | Variant summary: BRCA2 c.1296_1297delGA (p.Asn433GlnfsX18) 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. The variant was absent in 120444 control chromosomes (ExAC). The variant, c.1296_1297delGA, has been reported in the literature in individuals affected with either sporadic or Hereditary Breast and Ovarian Cancer (Wong-Brown 2015, Pritzlaff 2017, Meisel 2017, Lang 2017). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; 8 laboratories classified the variant as pathogenic, and 1 as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 21, 2024 | Criteria applied: PVS1,PM5_STR,PM2_SUP - |
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.Asn433GlnfsX18 variant was identified in 2 of 5484 proband chromosomes (frequency: 0.00036) from individuals or families with male breast cancer (Pritzlaff_2016_28008555), triple negative breast cancer (Wong-Brown_2015_25682074), and Lynch syndrome (Yurgelun_2017_28135145). The variant was also identified in dbSNP (ID: rs80359276) as “With Pathogenic allele”, ClinVar (as pathogenic reviewed by expert panel), Clinvitae (5x as [pathogenic), LOVD 3.0 (7x), UMD-LSDB (2x as causal), BIC Database (3x as pathogenic), and ARUP Laboratories (as definitely pathogenic) databases. The variant was not identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Asn433GlnfsX18 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 433 and leads to a premature stop codon at position 450. This alteration is then predicted to result in 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 | Oct 09, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 05, 2022 | The c.1296_1297delGA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 1296 to 1297, causing a translational frameshift with a predicted alternate stop codon (p.N433Qfs*18). This mutation was identified in a female diagnosed with triple negative breast cancer (Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80), and in a male diagnosed with breast cancer (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586). This alteration was identified in a cohort German patients considered to be at increased risk for HBOC syndrome (Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). In a large, clinic-based BRCA1/2 testing cohort in Norway, this variant was detected in one family (Heramb C et al. Hered Cancer Clin Pract. 2018 Jan;16:3). 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
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