rs80359627
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.6833_6837delTCTTA(p.Ile2278SerfsTer13) 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 (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.6833_6837delTCTTA | p.Ile2278SerfsTer13 | frameshift_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.6464_6468delTCTTA | p.Ile2155SerfsTer13 | frameshift_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.6833_6837delTCTTA | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4
Variant allele predicted to encode a truncated non-functional protein. -
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Hereditary breast ovarian cancer syndrome Pathogenic:3
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This sequence change creates a premature translational stop signal (p.Ile2278Serfs*13) 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: 8988179, 30103829). This variant is also known as c.7057del5. ClinVar contains an entry for this variant (Variation ID: 52203). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: BRCA2 c.6833_6837delTCTTA (p.Ile2278SerfsX13) 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 250196 control chromosomes. c.6833_6837delTCTTA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_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. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
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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 a personal or family history consistent with pathogenic variants in this gene (PMID: 22762150, 30103829, 32341426); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 7061_7065del; This variant is associated with the following publications: (PMID: 8988179, 12036913, 29446198, 22762150, 31853058, 32341426, 31341520, 30103829, 34072659, 33471991) -
Hereditary cancer-predisposing syndrome Pathogenic:2
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 been reported in at least 4 individuals affected with breast and ovarian cancer (PMID: 12036913, 30103829, 32341426, 33471991; Leiden Open Variation Database DB-ID BRCA2_003427, 34072659) and has been identified in 5 families among the CIMBA participants (PMID: 29446198). 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. -
The c.6833_6837delTCTTA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 6833 to 6837, causing a translational frameshift with a predicted alternate stop codon (p.I2278Sfs*13). This alteration has been identified in a breast and an ovarian cancer cohort (Gayther SA et al. Nat. Genet. 1997 Jan;15(1):103-5; Cardoso FC et al. Hum. Genomics. 2018 08;12(1):39). 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
The c.6833_6837del (p.Ile2278Serfs*13) variant in the BRCA2 gene is located on the exon 11 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Ile2278Serfs*13), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast/ovarian/prostate cancer (PMID: 30103829, 31853058, 32614418, 31341520, 27153395). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 52203) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.6833_6837del (p.Ile2278Serfs*13) variant of BRCA2 has been classified as pathogenic. -
Familial cancer of breast Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at