rs80359274
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.1278del(p.Asp427ThrfsTer3) variant causes a frameshift 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. E425E) has been classified as Benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.558
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 13-32332751-GA-G is Pathogenic according to our data. Variant chr13-32332751-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 51094.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332751-GA-G is described in Lovd as [Pathogenic]. Variant chr13-32332751-GA-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.1278del | p.Asp427ThrfsTer3 | frameshift_variant | 10/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.1278del | p.Asp427ThrfsTer3 | frameshift_variant | 10/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:8
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 51094). This variant is also known as 1506delA. This premature translational stop signal has been observed in individual(s) with Ewing sarcoma and breast and/or ovarian cancer (PMID: 24249303, 26822237). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asp427Thrfs*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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 27, 2019 | Variant summary: BRCA2 c.1278delA (p.Asp427ThrfsX3) 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 243654 control chromosomes. c.1278delA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (example, Nakamura_2013, Parsons_2016, Momozawa_2018 and Liu_2019). Many of these reports were in sequencing studies originating from Japanese cohorts (example, Momozawa_2018). These data indicate that the variant is likely to be associated with disease. No experimental evidence demonstrating an impact on protein function was ascertained. Four 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, 2 Pathogenic:2
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. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | May 13, 2020 | This variant deletes 1 nucleotide 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 individuals affected with breast cancer (PMID: 28090007, 30652428). 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 23, 2021 | The c.1278delA pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1278, causing a translational frameshift with a predicted alternate stop codon (p.D427Tfs*3). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in Japaense breast cancer cohorts, including a cohort of unselected male breast cancer patients (Kawahara M et al. J Hum Genet, 2004 May;49:391-395; Walsh MF et al. Cold Spring Harb Mol Case Stud, 2017 Nov;3:; Tozaki M et al. Magn Reson Med Sci, 2017 Jul;16:265-269; Yamauchi H et al. Breast Cancer Res Treat, 2018 Dec;172:679-687; Liu Y et al. Mol Genet Genomic Med, 2019 03;7:e493; Momozawa Y et al. Nat Commun, 2018 10;9:4083). In addition to the information 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. - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Computational scores
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SpliceAI score (max)
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