chr13-32355033-A-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.7180A>T(p.Arg2394Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,244 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R2394R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.7180A>T | p.Arg2394Ter | stop_gained | 14/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7180A>T | p.Arg2394Ter | stop_gained | 14/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74382
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5
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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Sep 06, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Oct 28, 2010 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 30, 2017 | Variant summary: The BRCA2 c.7180A>T (p.Arg2394X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52279). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer syndrome and breast and/or ovarian cancer, and pancreatic cancer (PMID: 15340362, 24065114, 25136594, 25366421, 28454591). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change creates a premature translational stop signal (p.Arg2394*) 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 | Mendelics | Jul 02, 2018 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 30, 2021 | 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Marroni 2004, Ratajska 2015, Fernandes 2016); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 7408A>T; This variant is associated with the following publications: (PMID: 26689913, 29625052, 30736435, 29446198, 17224268, 27836010, 29907814, 25366421, 27741520, 21990299, 24131973, 15340362, 25525159) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | BRCA2: PVS1, PM2, PS4:Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 28, 2018 | The variant creates a premature nonsense codon, and is therefore predicted to significantly disrupt the protein structure. Found in at least one symptomatic patient, and found in general population data that is consistent with pathogenicity. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 19, 2021 | The p.R2394* pathogenic mutation (also known as c.7180A>T), located in coding exon 13 of the BRCA2 gene, results from an A to T substitution at nucleotide position 7180. This changes the amino acid from an arginine to a stop codon within coding exon 13. This mutation has been detected in multiple hereditary breast and ovarian cancer (HBOC) syndrome families (Marroni F et al. Eur J Hum Genet, 2004 Nov;12:899-906; Manoukian S et al. Eur J Cancer, 2007 Feb;43:601-6; Bellacosa A et al. Cancer Prev Res (Phila), 2010 Jan;3:48-61; Yang D et al. JAMA, 2011 Oct;306:1557-65; Ratajska M et al. J Appl Genet, 2015 May;56:193-8; Rebbeck TR et al. Breast Cancer Res, 2016 11;18:112; Fernandes GC et al. Oncotarget, 2016 Dec;7:80465-80481; Hoyer J et al. BMC Cancer, 2018 Sep;18:926; Concolino P et al. Int J Mol Sci, 2019 Jul;20; Santonocito C et al. Cancers (Basel), 2020 May;12). This mutation has also been detected in patients with pancreatic cancer (Humphris JL et al. Gastroenterology, 2017 01;152:68-74.e2; Johns AL et al. Genome Med, 2017 04;9:41). Of note, this alteration is also designated as 7408A>T in published literature. 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 16, 2022 | This variant changes 1 nucleotide in exon 14 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 been reported in at least 5 individuals affected with breast and ovarian cancer (PMID: 24131973, 25136594, 25366421, 27836010) and an individual affected with pancreatic cancer (PMID: 34200245). 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. - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 07, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at