rs864622302
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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.1138del(p.Ser380ValfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,788 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: 0.0000034 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.223
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 13-32332614-GA-G is Pathogenic according to our data. Variant chr13-32332614-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 51070.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332614-GA-G is described in Lovd as [Pathogenic]. Variant chr13-32332614-GA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.1138del | p.Ser380ValfsTer19 | frameshift_variant | 10/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.1138del | p.Ser380ValfsTer19 | frameshift_variant | 10/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461788Hom.: 0 Cov.: 35 AF XY: 0.00000688 AC XY: 5AN XY: 727198
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35
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:15
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 | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 29, 2020 | The p.Ser380Valfs19 variant in BRCA2 has been reported in at least 7 Brazilian individuals with breast or ovarian cancer (PMID: 27741520, 27425403, 29161300, 29907814), and was absent from large population studies. This variant has also been reported pathogenic in ClinVar (Variation ID: 51070). This variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at position 380 and leads to a premature termination codon 19 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary susceptibility to breast and/or ovarian cancer. In summary, this variant meets criteria to be classified as pathogenic for hereditary susceptibility to breast and/or ovarian cancer in an autosomal dominant manner based on the predicted impact of the variant. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate (Richards 2015). - |
| 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, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Nov 25, 2022 | ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 supporting - |
| 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) | Jul 12, 2010 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 11, 2021 | This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 29907814 (2018), 29161300 (2017), 27425403 (2016), 18779604 (2008)).This variant has not been reported in large, multi-ethnic general populations. Internal laboratory data indicates that this variant was detected in an individual with a phenotype consistent with disease. Based on the available information, the variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 29, 2019 | 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; 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Alemar 2016, Fernandes 2016, Cerretini 2019); Also known as 1366delA; This variant is associated with the following publications: (PMID: 27741520, 28087643, 18779604, 28152038, 27425403, 10923033, 31446535, 29907814) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 06, 2022 | This variant deletes 1 nucleotide in exon 10 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 1366delA by BIC nomenclature and c.1137delA. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 18779604, 27425403, 27741520, 28087643, 29161300, 29907814, 31446535). 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 | Sep 21, 2021 | The c.1138delA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1138, causing a translational frameshift with a predicted alternate stop codon (p.S380Vfs*19). This pathogenic mutation has been reported in multiple families with a history of breast and/or ovarian cancer (Kurian AW et al. J Clin Oncol, 2008 Oct;26:4752-8; Alemar B et al. Cancer Genet, 2016 09;209:417-422; Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481; Afghahi A et al. Clin Cancer Res, 2017 07;23:3365-3370; Alemar B et al. PLoS One, 2017 Nov;12:e0187630; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Palmero EI et al. Sci Rep, 2018 06;8:9188; Cerretini R et al. Breast Cancer Res Treat, 2019 Dec;178:629-636; Nagy TR et al. Clinics (Sao Paulo) Jul 2021;76:e2837). Of note, this alteration is also designated as 1366delA 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 16, 2024 | This sequence change creates a premature translational stop signal (p.Ser380Valfs*19) 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 personal and/or family history of breast and/or ovarian cancer (PMID: 18779604). ClinVar contains an entry for this variant (Variation ID: 51070). 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 | Feb 04, 2022 | Variant summary: BRCA2 c.1138delA (p.Ser380ValfsX19) 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 250180 control chromosomes (gnomAD). c.1138delA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer (examples:Kurian_2008 and Alemar_2016) . One expert panel (ENIGMA) and eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Focal-onset seizure Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Jan 24, 2019 | - - |
BRCA2-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | The c.1138delA;p.(Ser380Valfs*19) 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: 51070; PMID:29907814; PMID: 29161300; PMID: 27741520; PMID: 27425403) - PS4. This variant is not present in population databases (rs80359264- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 09, 2023 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
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