rs80359593
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.6446_6450del(p.Ile2149SerfsTer25) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000694 in 1,439,916 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. I2149I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.01
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 13-32340799-TATTAA-T is Pathogenic according to our data. Variant chr13-32340799-TATTAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 52102.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340799-TATTAA-T is described in Lovd as [Pathogenic]. Variant chr13-32340799-TATTAA-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.6446_6450del | p.Ile2149SerfsTer25 | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.6446_6450del | p.Ile2149SerfsTer25 | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.94e-7 AC: 1AN: 1439916Hom.: 0 AF XY: 0.00000140 AC XY: 1AN XY: 715440
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4
| 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) | Dec 23, 2003 | - - |
| 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) | Apr 19, 2012 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
| 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 | Mar 14, 2021 | Variant summary: BRCA2 c.6446_6450delTTAAA (p.Ile2149SerfsX25) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 230326 control chromosomes. c.6446_6450delTTAAA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Coulet_2010, Dworkin_2009, Nakamura_2013, Lubinski_2004, Kanke_2018, Kwong_2015). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories, one expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 30, 2023 | This sequence change creates a premature translational stop signal (p.Ile2149Serfs*25) 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, 20858050). ClinVar contains an entry for this variant (Variation ID: 52102). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 05, 2019 | The BRCA2 c.6446_6450delTTAAA; p.Ile2149fs variant (rs80359593), also known as 6674del5, is reported in the literature in multiple individuals affected with hereditary breast and ovarian cancers (Dworkin 2009, Kanke 2017, Kwong 2016, Lubinski 2004, Nakamura 2015). This variant is reported in ClinVar (Variation ID: 52102), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 5 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several other downstream truncating variants have been reported in individuals with breast and ovarian cancers and are considered pathogenic Kwong 2016, Lubinski 2004, Nakamura 2015). Based on available information, this variant is considered to be pathogenic. References: Dworkin AM et al. Methylation not a frequent "second hit" in tumors with germline BRCA mutations. Fam Cancer. 2009;8(4):339-46. Kanke Y et al. Gene aberration profile of tumors of adolescent and young adult females. Oncotarget. 2017 Dec 29;9(5):6228-6237. 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. Nakamura S et al. Prevalence and differentiation of hereditary breast and ovarian cancers in Japan. Breast Cancer. 2015 Sep;22(5):462-8. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 01, 2020 | 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 (Lubinksi 2004, Dworkin 2009, Foley 2015, Nakamura 2015, Kanke 2018, Momozawa 2018); 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 6445_6449del5, 6674del5, or 6674_6678delTTAAA; This variant is associated with the following publications: (PMID: 31214711, 29176636, 19340607, 20858050, 24249303, 26023681, 26187060, 29464067, 30287823, 15131399) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 11, 2023 | The c.6446_6450delTTAAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 6446 to 6450, causing a translational frameshift with a predicted alternate stop codon (p.I2149Sfs*25). This pathogenic mutation has been reported in individuals with HBOC-related cancers (Lubinski J et al. Fam. Cancer. 2004;3(1):1-10; Dworkin AM et al. Fam. Cancer 2009 Apr;8(4):339-46; Foley SB et al. EBioMedicine 2015 Jan;2(1):74-81), and in Japanese breast cancer cohorts (Nakamura S et al. Breast Cancer 2015 Sep;22(5):462-8; Kwong A et al. J. Med. Genet. 2016 Jan;53(1):15-23; Momozawa Y et al. Nat. Commun. 2018 10;9(1):4083). Of note, this alteration is also designated as 6674del5 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant deletes 5 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. 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. - |
Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 13, 2022 | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 21, 2022 | - - |
Computational scores
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