13-32319283-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.274C>T(p.Gln92*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 stop_gained
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.274C>T | p.Gln92* | stop_gained | Exon 3 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893 | c.-96C>T | 5_prime_UTR_variant | Exon 3 of 27 | 1 | ENSP00000499438.2 | ||||
| BRCA2 | ENST00000614259.2 | n.274C>T | non_coding_transcript_exon_variant | Exon 2 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Pathogenic:4
Variant summary: BRCA2 c.274C>T (p.Gln92X) 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 251214 control chromosomes. c.274C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Kluska_2015, Wojcik_2016, Zhang_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. Some submitters cite overlapping evidence utilized in the context of this evaluation. All submitters classified the variant as pathogenic in the germline and somatic settings. Based on the evidence outlined above, the variant was classified as pathogenic. -
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This sequence change creates a premature translational stop signal (p.Gln92*) 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 variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 37799). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3
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Variant allele predicted to encode a truncated non-functional protein. -
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not provided Pathogenic:3
Nonsense 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 502C>T; This variant is associated with the following publications: (PMID: 27257965, 26843898, 32377563, 31825140, 31853058, 20104584, 25948282, 30287823) -
The BRCA2 c.274C>T; p.Gln92Ter variant (rs80358529) is reported in the literature in individuals affected with or a family history of breast and/or ovarian cancer (Kluska 2015, Perez-Ibave 2023). This variant is reported in ClinVar (Variation ID: 37799). The p.Gln92Ter variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and 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: Kluska A et al. New recurrent BRCA1/2 mutations in Polish patients with familial breast/ovarian cancer detected by next generation sequencing. BMC Med Genomics. 2015 May 7;8:19. PMID: 25948282. Perez-Ibave DC et al. Identification of Germline Variants in Patients with Hereditary Cancer Syndromes in Northeast Mexico. Genes (Basel). 2023 Jan 28;14(2):341. PMID: 36833268. -
This nonsense variant 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, the variant has been reported in individuals with breast cancer (PMIDs: 30287823 (2018), 26843898 (2016), 25948282 (2015)). Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant changes 1 nucleotide in exon 3 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. 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 p.Q92* pathogenic mutation (also known as c.274C>T), located in coding exon 2 of the BRCA2 gene, results from a C to T substitution at nucleotide position 274. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This alteration was reported in a patient from a Polish cohort of women with early onset or familial breast and/or ovarian cancer (Kluska A et al. BMC Med Genomics, 2015 May;8:19). 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. -
Breast neoplasm Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at