rs80358427
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.1399A>T(p.Lys467Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,898 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. K467K) 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.1399A>T | p.Lys467Ter | stop_gained | 10/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.1399A>T | p.Lys467Ter | stop_gained | 10/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247228Hom.: 0 AF XY: 0.00000748 AC XY: 1AN XY: 133638
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1458898Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 725560
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Dec 23, 2003 | - - |
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 | Sharing Clinical Reports Project (SCRP) | Jul 06, 2010 | - - |
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 | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 02, 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 found in general population data at a frequency that is consistent with pathogenicity. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 27, 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; 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 (Lek 2016); Also known as 1627A>T; This variant is associated with the following publications: (PMID: Dong2015, 16455195, 28724667, 30716324, 30350268, 29176636, 32029870, 12204006, 22217648, 21497495, 17100994, 25011685, 16949048, 22798144, 23593081, 26187060, 21847643, 25525159, 25856671, 26295337, 29093764, 28205045, 28351343, 29346284, 27257965, 29020732, 29752822, 30652428, 30287823, 28111427, 29446198, 30720243, 30702160, 31825140, 31742824) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 17, 2021 | The p.K467* pathogenic mutation (also known as c.1399A>T), located in coding exon 9 of the BRCA2 gene, results from an A to T substitution at nucleotide position 1399. This changes the amino acid from a lysine to a stop codon within coding exon 9. This mutation has been reported in multiple Korean families affected with breast and/or ovarian cancer (Kang HC et al. Hum. Mutat. 2002 Sep;20(3):235; Ahn S et al. Cancer Lett. 2007 Jan 8;245(1-2):90-5; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134(3):1315-26; Eoh KJ et al. Cancer Res Treat. 2018 Jul;50(3):917-925). This mutation was also detected in a single individual of Han Chinese descent with triple negative breast cancer diagnosed at 42 (Ou J et al. J. Breast Cancer. 2013 Mar;16(1):50-4). Of note, this alteration is also designated as 1627A>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 | Jan 15, 2020 | This variant changes 1 nucleotide in exon 10 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 identified in 1/247228 chromosomes 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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 04, 2021 | Variant summary: BRCA2 c.1399A>T (p.Lys467X) 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 allele was found at a frequency of 4e-06 in 247228 control chromosomes. c.1399A>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Kang_2002, Ahn_2007, and Pak_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 13, 2023 | This sequence change creates a premature translational stop signal (p.Lys467*) 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 present in population databases (rs80358427, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer (PMID: 12204006, 16455195, 22798144, 26848529, 27257965, 27836010). This variant is also known as c.1627A>T. ClinVar contains an entry for this variant (Variation ID: 51118). For these reasons, this variant has been classified as Pathogenic. - |
Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Breast neoplasm Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University | Nov 01, 2015 | - - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 25, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at