chr13-32332667-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.1189C>T(p.Gln397Ter) 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. Q397Q) has been classified as Likely benign. 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.1189C>T | p.Gln397Ter | stop_gained | 10/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.1189C>T | p.Gln397Ter | stop_gained | 10/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:2
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. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 12, 2018 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 03, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 236829). This premature translational stop signal has been observed in individual(s) with BRCA2-related conditions (PMID: 21520333). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln397*) 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 | Sep 05, 2023 | Variant summary: BRCA2 c.1189C>T (p.Gln397X) 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. The variant was absent in 250170 control chromosomes. c.1189C>T has been reported in the literature in at least two individuals affected with clinical features of BRCA2-related conditions (e.g., Akcay_2021). The following publication has been ascertained in the context of this evaluation (PMID: 32658311). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic or likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 10, 2020 | The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 11, 2021 | The p.Q397* pathogenic mutation (also known as c.1189C>T), located in coding exon 9 of the BRCA2 gene, results from a C to T substitution at nucleotide position 1189. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). 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
Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This variant is a single amino acid change from Glutamine to a premature translational stop signal at codon 397 of the BRCA2 protein. This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant has been described in the international literature in an individual undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 236829). - |
Breast carcinoma Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 16, 2021 | Invasive Ductal Carcinoma - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at