rs80359489
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.5158dupT(p.Ser1720PhefsTer7) 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.5158dupT | p.Ser1720PhefsTer7 | frameshift_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.4789dupT | p.Ser1597PhefsTer7 | frameshift_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.5158dupT | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 46
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5
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The BRCA2 c.5158dup p.(Ser1720PhefsTer7) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported in the literature in individuals with breast and/or ovarian cancer (PMID: 25186627; 25395318; 21324516). Additionally, other well-known, pathogenic truncating variants have been identified that affect the same exon of BRCA2. This variant is not observed in version 2.1.1 or version 4.0.0 of the Genome Aggregation Database. Based on the available evidence, the c.5158dup p.(Ser1720PhefsTer7) variant is classified as pathogenic for hereditary breast and ovarian cancer. -
Variant allele predicted to encode a truncated non-functional protein. -
Hereditary breast ovarian cancer syndrome Pathogenic:5
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This sequence change creates a premature translational stop signal (p.Ser1720Phefs*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 breast and/or ovarian cancer (PMID: 21324516, 25395318, 26219728). This variant is also known as c.5158_5159insT and 5386insT. ClinVar contains an entry for this variant (Variation ID: 51781). For these reasons, this variant has been classified as Pathogenic. -
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Variant summary: BRCA2 c.5158dupT (p.Ser1720PhefsX7) 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 228554 control chromosomes. c.5158dupT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). 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. Multiple clinical diagnostic laboratories and one expert panel (ENIGMA) 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:4
This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals with breast and/or ovarian cancer in the published literature (PMID: 25186627 (2015), 25395318 (2014), 21324516 (2011), 19714488 (2009)). This variant has not been reported in large, multi-ethnic general populations. Therefore, the variant is classified as pathogenic. -
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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; 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 21324516, 25395318, 26219728); Also known as 5386dupT; This variant is associated with the following publications: (PMID: 19714488, 25186627, 28888541, 25395318, 21324516, 26219728, 28152038, 32438681, 30787465, 29446198, 36623239) -
The BRCA2 c.5158dupT; p.Ser1720PhefsTer7 variant (rs80359489), also known as 5386dup in traditional nomenclature, is reported in the literature in several individuals and families affected with breast and/or ovarian cancer (Coppa 2014, Finch 2016, Rebbeck 2018, Santonocito 2020, Tung 2015). This variant is also reported in ClinVar (Variation ID: 51781) and is classified as pathogenic by the evidence-based network for the interpretation of germline mutant alleles (ENIGMA) expert panel (see link to ENIGMA consortium classification criteria). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Link to ENIGMA classification criteria: https://enigmaconsortium.org/library/general-documents/enigma-classification-criteria/ Coppa A et al. Novel and recurrent BRCA2 mutations in Italian breast/ovarian cancer families widen the ovarian cancer cluster region boundaries to exons 13 and 14. Breast Cancer Res Treat. 2014 Dec;148(3):629-35. PMID: 25395318. Finch A et al. Genetic testing for BRCA1 and BRCA2 in the Province of Ontario. Clin Genet. 2016 Mar;89(3):304-11. PMID: 26219728. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. PMID: 29446198. Santonocito C et al. Spectrum of Germline BRCA1 and BRCA2 Variants Identified in 2351 Ovarian and Breast Cancer Patients Referring to a Reference Cancer Hospital of Rome. Cancers (Basel). 2020 May 19;12(5):1286. PMID: 32438681. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. PMID: 25186627. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant inserts 1 nucleotide 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 individuals affected with breast and/or ovarian cancer (PMID: 19714488, 21324516, 25186627, 25395318, 26219728, 32438681). 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.5158dupT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 5158, causing a translational frameshift with a predicted alternate stop codon (p.S1720Ffs*7). This mutation has been reported in an individual of Italian descent from a cohort of 1342 unselected women with invasive epithelial ovarian tumors (Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7). This alteration was detected in a breast-ovarian cancer family from Italy and resides in the ovarian cancer cluster region (OCCR) of BRCA2 (Coppa A et al. Breast Cancer Res.Treat. 2014 Dec;148(3):629-35). This alteration was also detected on a 25-gene panel test in a woman who was diagnosed with breast cancer before age 50 of Western/ Northern European ancestry (Tung N et al. Cancer. 2015 Jan;121:25-33). Of note, this alteration is also referred to as 5386insT and c.5158_5159insT in the published literature. 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. -
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