rs80357461
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3904G>T(p.Glu1302Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 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. E1302E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_007294.4 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 |
---|---|---|---|---|---|---|---|
BRCA1 | NM_007294.4 | c.3904G>T | p.Glu1302Ter | stop_gained | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.3904G>T | p.Glu1302Ter | stop_gained | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461878Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727240
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
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) | May 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM2_supporting; PM5_PTC_Strong - |
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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 09, 2018 | The p.Glu1302X variant in BRCA1 has been reported in at least 3 individuals with breast cancer, and segregated with disease in one affected relative (Casadei 2001, Nielsen 2016, Ramus 2017). In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000300040.2) and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1302 which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in hereditary breast and ovariant cancer. In summary, this variant meets criteria to be classified as pathogenic for hereditary breast and ovarian cancer in an autosomal dominant manner based case reports, absence from controls and predicted impact on protein. ACMG/AMP Criteria applied: PM2,PVS1, PS4_Supporting. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change creates a premature translational stop signal (p.Glu1302*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 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 cancer (PMID: 17688236). ClinVar contains an entry for this variant (Variation ID: 55045). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 24, 2023 | Variant summary: BRCA1 c.3904G>T (p.Glu1302X) 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 251170 control chromosomes. c.3904G>T has been reported in the literature in multiple individuals affected with or with family history of Hereditary Breast And Ovarian Cancer Syndrome (HBOC) (e.g. Judkins_2005, Lecarpentier_2012, Ramus_2007, Sirchia_2005, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (e.g. Sirchia_2005). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 04, 2023 | 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; 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 personal or family history of breast or ovarian cancer (Casadei et al., 2001; Judkins et al., 2005; Ramus et al., 2007; Nielsen et al., 2016); Also known as 4023G>T; This variant is associated with the following publications: (PMID: 19826428, 25525159, 17688236, 16267036, 26833046, 22762150, 32854451, 29446198, 11556835, 15781624, 30128899, 33403015, 33471991, 31209999, 31853058, 29884841, 32377563, 37460658, 32380732) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 11, 2021 | The p.E1302* pathogenic mutation (also known as c.3904G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 3904. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This alteration has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Ramus SJ et al. Hum. Mutat. 2007 Dec; 28(12):1207-15; Nielsen HR et al. Fam. Cancer 2016 Feb; Marchetti C et al. Ann Surg Oncol, 2018 Nov;25:3701-3708; Fanale D et al. Cancers (Basel), 2020 Aug;12:; Incorvaia L et al. Ther Adv Med Oncol, 2020 Dec;12:1758835920975326; Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). 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. - |
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 BRCA1 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 BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at