13-32338764-TAAGA-T
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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.4415_4418del(p.Lys1472ThrfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,457,966 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.860
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 13-32338764-TAAGA-T is Pathogenic according to our data. Variant chr13-32338764-TAAGA-T is described in ClinVar as [Pathogenic]. Clinvar id is 37902.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338764-TAAGA-T is described in Lovd as [Pathogenic]. Variant chr13-32338764-TAAGA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.4415_4418del | p.Lys1472ThrfsTer6 | frameshift_variant | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.4415_4418del | p.Lys1472ThrfsTer6 | frameshift_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.00000402 AC: 1AN: 248584Hom.: 0 AF XY: 0.00000744 AC XY: 1AN XY: 134498
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GnomAD4 exome AF: 0.0000165 AC: 24AN: 1457966Hom.: 0 AF XY: 0.0000193 AC XY: 14AN XY: 724540
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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:6
| 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, 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 | Molecular Endocrinology Laboratory, Christian Medical College | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Nov 14, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
not provided Pathogenic:4
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Lys1472Thrfs*6 variant was identified in 6 of 2414 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome, breast, or ovarian cancer (Hansen 2017, Karami 2013, Konstantopoulou 2014, Lubinski 2004, Pietschmann 2005). The variant was also identified in dbSNP (ID: rs397507333) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, GeneDx and six other submitters), LOVD 3.0 (7x as pathogenic), and in ARUP Laboratories (as definitely pathogenic) databases. The variant was not identified in COGR, Cosmic, UMD-LSDB, BIC Database, or Zhejiang University databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.4415_4418del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1472 and leads to a premature stop codon at position 1477. 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 BRCA2 associated cancers 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 20, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 26, 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; Observed in individuals with BRCA2-related cancers (Pietschmann et al., 2005; Konstantopoulou et al., 2014; Eccles et al., 2016; Ashour et al., 2019; Deng et al., 2019); 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 4643_4646del, 4643_4646delAGAA, 4643del4, or 4643delAGAA; This variant is associated with the following publications: (PMID: 26681682, 29922827, 34687993, 29752822, 30720243, 30972954, 31372034, 15918047, 24010542, 19877752, 19139771, 24312913, 15131399, 26295337, 28195393, 26109977, 26300996, 31825140, 33087929, 20104584, 33632156) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 02, 2018 | Variant summary: BRCA2 c.4415_4418delAGAA (p.Lys1472ThrfsX6) 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 allele was found at a frequency of 4.1e-06 in 243794 control chromosomes (gnomAD and publications). c.4415_4418delAGAA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lubinski 2004, Pietschmann 2005, Konstantopoulou 2014, Eccles 2016). 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| 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 | Labcorp Genetics (formerly Invitae), Labcorp | Jan 17, 2024 | This sequence change creates a premature translational stop signal (p.Lys1472Thrfs*6) 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 (rs748716604, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and breast and/or ovarian cancer (PMID: 15131399, 15918047, 24010542, 26681682, 28195393). ClinVar contains an entry for this variant (Variation ID: 37902). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 14, 2019 | The p.Lys1472ThrfsX6 variant in BRCA2 has been reported in at least 5 individuals with BRCA2-related cancers (Hansen 2017, Li 2018, Pietschmann 2005, Konstantopoulou 2014). It has also been identified in 1/112594 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 is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1472 and leads to a premature termination codon 6 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sept 8 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37902). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. - |
Familial cancer of breast Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 28, 2023 | The c.4415_4418delAGAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 4415 to 4418, causing a translational frameshift with a predicted alternate stop codon (p.K1472Tfs*6). This pathogenic mutation, also designated as 4643del4, is located in the ovarian cancer cluster region (OCCR) and has been reported in multiple families with HBOC related cancers (Lubinski J et al. Fam Cancer. 2004;3(1):1-10; Pietschmann A et al. J. Cancer Res. Clin. Oncol.2005 Aug;131(8):552-8; Karami F and Mehdipour P. Biomed Res Int. 2013;2013:928562). 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 02, 2020 | This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and 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: 15918047, 24010542, 24312913, 26681682, 27153395) or colorectal cancer (PMID: 28195393). This variant has been identified in 1/248584 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. - |
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 | Aug 16, 2024 | Criteria applied: PVS1,PM5_STR,PM2_SUP - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 09, 2020 | - - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Computational scores
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