rs80356978
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2722G>T(p.Glu908Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,652 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 (★★★). 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.2722G>T | p.Glu908Ter | stop_gained | 10/23 | ENST00000357654.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA1 | ENST00000357654.9 | c.2722G>T | p.Glu908Ter | stop_gained | 10/23 | 1 | NM_007294.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461652Hom.: 0 Cov.: 51 AF XY: 0.00000275 AC XY: 2AN XY: 727110
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:12
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, 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, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA1) | May 29, 2002 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 02, 2012 | - - |
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Oct 24, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 08, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 24, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 27, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Feb 01, 2019 | The c.2722G>T (p.Glu908*) variant in the BRCA1 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple individuals affected with breast or ovarian cancer (PMID 8554067, 19016756, 19949876, 22006311, 22009639, 25880076). This variant is not observed in gnomAD database. Therefore, the c.1953_1956delGAAA (p.Lys653Serfs*47) variant in the BRCA1 gene is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | 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 been reported in multiple individuals affected with breast cancer, ovarian cancer and glioblastoma (PMID: 19016756, 22006311, 25880076, 26010302, 29470806, 32380732, 33471991, 35625946). 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. - |
not provided Pathogenic:7Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 25, 2020 | 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 (Serova 1996, Sugano 2008, Boukerroucha 2015, Conroy 2017); Not observed in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 2841G>T; This variant is associated with the following publications: (PMID: 26010302, 25722380, 28152038, 22006311, 8554067, 22009639, 24055113, 25880076, 25637381, 10553024, 9150151, 19016756, 25452441, 18465347, 16615107, 20104584, 19949876, 14574155, 9465809, 16528604, 9667259, 12393792, 25504618, 24549055, 27767231, 28959512, 29907814, 29470806, 28724667, 30702160, 29446198, 28176296, 25525159, 31825140, 31742824, 11597388) - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This is a single base substitution, replacing the Glutamate at position 908 of the BRCA1 protein by a Termination codon. It is expected to result in an absent or disrupted protein product. Truncating variants in BRCA1 are known to be pathogenic. The mutation database ClinVar contains entries for this variant (Variation ID: 54657). - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 13, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Apr 13, 2021 | This nonsense variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals and families affected with breast/ovarian cancer (PMIDs: 12393792 (2002), 12068003 (2002), 29470806 (2018), 29907814 (2018), 32380732 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2018 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 04, 2016 | The p.Glu908X variant in BRCA1 has been reported in >60 individuals with BRCA1-a ssociated cancers (Serova 1996, Couch 2015, Boukerroucha 2015, Breast Cancer Inf ormation Core (BIC), Sharing Clinical Reports Project). This variant has been id entified in 1/8600 European chromosomes by the NHLBI Exome Sequencing Project (h ttp://evs.gs.washington.edu/EVS/; dbSNP rs80356978). This nonsense variant leads to a premature termination codon at position 908, 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 individuals with hereditary breast and ov arian cancer (HBOC). In addition, this variant was classified as Pathogenic on S eptember 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV0002998 19.2). In summary, this variant meets our criteria to be classified as pathogeni c for HBOC in an autosomal dominant manner. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change creates a premature translational stop signal (p.Glu908*) 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 and ovarian cancer and glioblastoma (PMID: 8554067, 19016756, 19949876, 25880076). This variant is also known as 2841G>T. ClinVar contains an entry for this variant (Variation ID: 54657). For these reasons, this variant has been 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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 15, 2016 | Variant summary: The BRCA1 c.2722G>T (p.Glu908X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. If a stable protein is made, Glu908X is predicted to eliminate the BRCT domain. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Val923fsX76, p.Asp936fsX63, etc.). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/121362 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant was cited in multiple HBOC patients in the literature and was shown to co-segregate with disease. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 08, 2023 | 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 been reported in multiple individuals affected with breast cancer, ovarian cancer and glioblastoma (PMID: 19016756, 22006311, 25880076, 26010302, 29470806, 32380732, 33471991, 35625946). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 09, 2022 | The p.E908* pathogenic mutation (also known as c.2722G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2722. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This mutation has been reported in multiple breast and ovarian cancer (HBOC) syndrome kindreds to date (Serova O et al. Am. J. Hum. Genet. 1996 Jan;58:42-51; Walsh T et al. Proc. Natl. Acad. Sci. USA. 2011 Nov;108:18032-7; Boukerroucha M et al. BMC Cancer. 2015 Mar;15:181; De Brakeleer S et al. Clin. Genet.. 2016 Mar;89:336-40; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196). 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. - |
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Oct 01, 2001 | - - |
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Breast neoplasm Pathogenic:1
Pathogenic, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at