rs80359672
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.7673_7674del(p.Glu2558ValfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,448 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: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.34
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 13-32357794-CAG-C is Pathogenic according to our data. Variant chr13-32357794-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 38113.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357794-CAG-C is described in Lovd as [Pathogenic]. Variant chr13-32357794-CAG-C is described in Lovd as [Pathogenic]. Variant chr13-32357794-CAG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.7673_7674del | p.Glu2558ValfsTer7 | frameshift_variant | 16/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.7673_7674del | p.Glu2558ValfsTer7 | frameshift_variant | 16/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461448Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727038
GnomAD4 exome
AF:
AC:
1
AN:
1461448
Hom.:
AF XY:
AC XY:
1
AN XY:
727038
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14
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 | Department of Medical Genetics, Oslo University Hospital | Jul 01, 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, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 13, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 16, 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 personal and/or family history of BRCA2-related cancers (Lubinski 2004, van der Hout 2006, Bolognesi 2014, Ricci 2014, Kwong 2016, Wen 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 7901delAG; This variant is associated with the following publications: (PMID: 15131399, 26187060, 25415331, 16683254, 24307375, 24065114, 29339979, 28993434, 27083178, 31825140) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 19, 2022 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 11, 2024 | This sequence change creates a premature translational stop signal (p.Glu2558Valfs*7) 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 personal or family history of breast and/or ovarian cancer (PMID: 15131399, 16683254, 26187060, 27083178, 28993434, 29339979, 31209999). This variant is also known as 7901delAG. ClinVar contains an entry for this variant (Variation ID: 38113). For these reasons, this variant has been 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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 10, 2019 | Variant summary: BRCA2 c.7673_7674delAG (p.Glu2558ValfsX7) 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 251218 control chromosomes (gnomAD). c.7673_7674delAG has been reported in the literature in individuals/families affected with Hereditary Breast and Ovarian Cancer (Lubinski_2004, Ricci_2014, van der Hout_2006, Heramb_2018). 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 other submitters, including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 28, 2021 | This variant deletes 2 nucleotides in exon 16 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 detected in at least four individuals affected with breast cancer (PMID: 26187060, 27083178, 30287823; Color internal data) and in suspected hereditary breast and ovarian cancer families and a suspected hereditary cancer family (PMID: 15131399, 16683254, 24065114, 29339979). 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 | Nov 02, 2021 | The c.7673_7674delAG pathogenic mutation, located in coding exon 15 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 7673 to 7674, causing a translational frameshift with a predicted alternate stop codon (p.E2558Vfs*7). This mutation has been reported in the literature in multiple individuals/families with breast and/or ovarian cancer (Lubinkski, J et al. Fam Cancer. 2004;3(1):1-10; van der Hout AH et al. Hum. Mutat. 2006 Jul;27:654-66; Kwong A et al. J. Med. Genet. 2016 Jan;53:15-23; 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. - |
BRCA2-related cancer predisposition Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Aug 31, 2024 | The c.7673_7674del variant in the BRCA2 gene is located on exon 16 and is predicted to shift the reading frame that introduces a premature translation termination codon (p.Glu2558Valfs*7), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast and/or ovarian cancer (PMID: 27083178, 34657357, 30287823, 31825140, 31853058, 32776218). Premature translation termination codon variants located in the same exon (p.Gln2561*, p.Trp2586*) have been classified as pathogenic (ClinVar ID: 52386, 38116). Loss-of-function variants in the BRCA2 gene are known to cause hereditary breast and ovarian cancer (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar (ID: 38113) and interpreted as pathogenic by the expert panel. The variant is not observed in the general population database according to gnomAD. Therefore, the c.7673_7674del (p.Glu2558Valfs*7) variant in the BRCA2 gene has been classified as pathogenic. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 23, 2017 | - - |
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
DS_AG_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at