rs276174859
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.5609_5610delinsAG(p.Phe1870Ter) variant causes a stop gained 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. F1870F) has been classified as Likely benign. 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
Not classified
Clinical Significance
Conservation
PhyloP100: 0.153
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 13-32339964-TC-AG is Pathogenic according to our data. Variant chr13-32339964-TC-AG is described in ClinVar as [Pathogenic]. Clinvar id is 51890.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.5609_5610delinsAG | p.Phe1870Ter | stop_gained | 11/27 | ENST00000380152.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.5609_5610delinsAG | p.Phe1870Ter | stop_gained | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:16
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 | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Mar 05, 2020 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 17, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Sep 14, 2021 | - - |
| 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. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 21, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 12, 2024 | 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 5837_5838delTCinsAG; This variant is associated with the following publications: (PMID: 27003155, 21232165, 22923021, 28056804, 28324225, 16683254, 25447315, 16825431, 24156927, 22729890, 25583207, 23583677, 15689453, 28152038, 28288110, 24301060, 16115142, 15645491, 21719596, 30322717, 32341426, 33471991, 29446198, 36721989, 38219492, 18284688, 34680878, 12065746) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 12, 2022 | 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 cancer (PMID: 18284688, 21232165, 22729890, 28324225, 34680878) and Fanconi anemia (PMID: 12065746). In a large breast cancer case-control study conducted by the Breast Cancer Association Consortium, this variant was reported in 2/60466 cases and 0/53461 controls (p-value=0.502) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001645). 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 | Jun 05, 2018 | The c.5609_5610delTCinsAG pathogenic mutation (also known as p.F1870*), located in coding exon 10 of the BRCA2 gene, results from an in-frame deletion of TC and insertion of AG at nucleotide positions 5609 to 5610. This changes the amino acid from a phenylalanine to a stop codon within coding exon 10. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome families to date (Stegel V et al. BMC Med. Genet. 2011 Jan;12:9; Becker AA et al. Breast Cancer Res. Treat. 2012 Aug;135:167-75; Tea MK et al. Maturitas 2014 Jan;77:68-72; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238), and in an individual with Fanconi Anemia (Howlett NG et al. Science 2002 Jul;297:606-9). Of note, this alteration is also designated as 5837TC>AG in published 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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 19, 2024 | This sequence change creates a premature translational stop signal (p.Phe1870*) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with a personal or family history of breast and/or ovarian cancer and Fanconi anemia (PMID: 12065746, 21232165, 22729890, 22923021, 24156927). This variant is also known as 5837 TC to AG. ClinVar contains an entry for this variant (Variation ID: 51890). 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 | Apr 21, 2023 | Variant summary: BRCA2 c.5609_5610delinsAG (p.Phe1870X) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 247384 control chromosomes. c.5609_5610delinsAG has been reported in the literature in individuals and families affected with Hereditary Breast And Ovarian Cancer Syndrome (Becker_2012, Novakovic_2012, Stegel_2011, Tea_2014) and observed in a compound heterozygous Fanconi Anemia patient (Howlett_2002). 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. 12 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. - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
BAP1-related tumor predisposition syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 29, 2015 | The c.5609_5610delTCinsAG pathogenic mutation (also known as p.F1870* and 5837TC>AG), located in coding exon 10 of the BRCA2 gene, results from the deletion and insertion of 2 nucleotides at positions 5609 and 5610. This changes the amino acid at codon 1870 from a phenylalanine to a stop codon. This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome families to date (Stegel et al. BMC Med Genet. 2011 Jan 14;12:9; Becker et al. Breast Cancer Res Treat. 2012 Aug;135(1):167-75; Tea MK et al. Maturitas. 2014 Jan;77(1):68-72) and in an individual with Fanconi Anemia (Howlett et al. Science. 2002 Jul 26;297(5581):606-9). In addition to the clinical data presented in the literature, since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Fanconi anemia complementation group D1 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 26, 2002 | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 21, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at