rs80359283
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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.1389_1390del(p.Val464GlyfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,534 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: 0.0000027 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.281
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 13-32332866-CAG-C is Pathogenic according to our data. Variant chr13-32332866-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 51113.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332866-CAG-C is described in Lovd as [Pathogenic]. Variant chr13-32332866-CAG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.1389_1390del | p.Val464GlyfsTer3 | frameshift_variant | 10/27 | ENST00000380152.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.1389_1390del | p.Val464GlyfsTer3 | frameshift_variant | 10/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1459534Hom.: 0 AF XY: 0.00000276 AC XY: 2AN XY: 725894
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GnomAD4 genome
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Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:18
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 26, 2023 | This variant deletes 2 nucleotides in exon 10 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 been reported in at least 5 individuals affected with breast or ovarian cancer, including 2 male individuals (PMID: 21190077, 22711857, 24549055, 30287823, 34490083) and has been identified in 27 families among the CIMBA participants (PMID: 29446198). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 4/60466 cases and 2/53461 controls (OR=1.768 (95%CI 0.324 to 9.655); p-value=0.691) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001848). 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 | 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) | Apr 22, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Biomedical Genomics and Oncogenetics Laboratory, Institut Pasteur de Tunis, University Tunis El Manar | - | - - |
not provided Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2018 | This deletion of 2 nucleotides in BRCA2 is denoted c.1389_1390delAG at the cDNA level and p.Val464GlyfsX3 (V464GfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAAC[delAG]TGGT. The deletion causes a frameshift, which changes a Valine to a Glycine at codon 464, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.1389_1390delAG, also published as BRCA2 1617_1618delAG or BRCA2 1617delAG using alternate nomenclature, has been reported in association with Hereditary Breast and Ovarian cancer (Goelen 1999, Claes 2004, Machackova 2008). We consider this variant to be pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 01, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 01, 2023 | The BRCA2 c.1389_1390del (p.Val464Glyfs*3) variant (also known as 1617delAG) alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, this variant has been reported in multiple individuals with breast/ovarian cancer (PMIDs: 34490083 (2021), 31159747 (2019), 31263054 (2019), 30287823 (2018), 30322717 (2018), 26681312 (2015), 18489799 (2008), 16683254 (2006), 10227398 (1999)). Based on the available information, this variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 28, 2022 | The c.1389_1390delAG pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of two nucleotides between nucleotide positions 1389 and 1390, causing a translational frameshift with a predicted alternate stop codon (p.V464Gfs*3). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This mutation was reported in one Belgian family affected with both breast and ovarian cancer (Goelen G et al. J. Med. Genet. 1999 Apr;36(4):304-8), one Japanese male breast cancer patient (Momozawa Y et al. Nat Commun. 2018 10;9:4083), and in Czech families considered high-risk for breast and ovarian cancer (Foretova L et al. Hum. Mutat. 2004 Apr;23(4):397-8; Machackova E et al. BMC Cancer 2008 May;8:140). This alteration was identified in 1/10,030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 08;18:823-32). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). Of note, this alteration is also designated as 1617delAG, c.1617_1618delAG, and c.1389_1390del2 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 | curation | Sema4, Sema4 | Jan 09, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 19, 2023 | This variant deletes 2 nucleotides in exon 10 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 been reported in at least 5 individuals affected with breast or ovarian cancer, including 2 male individuals (PMID: 21190077, 22711857, 24549055, 30287823, 34490083) and has been identified in 27 families among the CIMBA participants (PMID: 29446198). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 4/60466 cases and 2/53461 controls (OR=1.768 (95%CI 0.324 to 9.655); p-value=0.691) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001848). 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. - |
Familial cancer of breast Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 05, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This sequence change deletes 2 nucleotide in exon 10 of the BRCA2 mRNA (c.1389_1390delAG), causing a frameshift after codon 464 and the creation of a premature translational stop signal 3 amino acid residues later (p.Val464Glyfs*3). This is expected to result in a truncated or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This particular truncation has been reported in the literature in families affected with breast and ovarian cancer (PMID: 10227398 ; Hum Mutat. 2004, 23:397-8; PMID: 16683254 ;PMID: 24549055). The mutation database ClinVar contains an entry for this variant (Variation ID: 51113). - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 01, 2021 | Variant summary: BRCA2 c.1389_1390delAG (p.Val464GlyfsX3) 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 248414 control chromosomes (gnomAD). c.1389_1390delAG has been reported in the literature in multiple individuals affected with breast- and/or ovarian cancer (e.g. Goelen_1999, Foretova_2004, Claes_2004, Susswein_2015, Delgado_2011, Rebbeck_2018, Dorling_2021). 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. Eight other submitters, including an 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change creates a premature translational stop signal (p.Val464Glyfs*3) 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 ovarian cancer (PMID: 10227398, 15024741, 16683254, 24549055, 26681312). This variant is also known as 1617delAG. ClinVar contains an entry for this variant (Variation ID: 51113). For these reasons, this variant has been classified as Pathogenic. - |
BRCA2-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | The c.1389_1390del;p.(Val464Glyfs*3) is a null frameshift variant (NMD) in the BRCA2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 51113; PMID: 10227398; PMID: 24549055; PMID: 16683254; PMID: 15024741; PMID: 26681312; PMID: 29446198). PS4. This variant is not present in population databases (rs80359283- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Computational scores
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Details are displayed if max score is > 0.2
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