Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2263G>T(p.Glu755*) 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 (★★★). Variant results in nonsense mediated mRNA decay.
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Pathogenic. The variant received 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-43093268-C-A is Pathogenic according to our data. Variant chr17-43093268-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 54516.Status of the report is reviewed_by_expert_panel, 3 stars.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Mar 28, 2023
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
PS4_MOD, PVS1, PM2_SUP -
Oct 31, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
The BRCA1 c.2263G>T (p.Glu755*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in individuals and/or families affected with breast and/or ovarian cancer (PMID: 9150174 (1997), 15024741 (2004), 18489799 (2008), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). 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. -
May 27, 2022
Clinical Genetics Laboratory, Skane University Hospital Lund
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
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Hereditary breast ovarian cancer syndromePathogenic:2
Aug 28, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This sequence change creates a premature translational stop signal (p.Glu755*) 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/or ovarian cancer (PMID: 9150174, 29446198). ClinVar contains an entry for this variant (Variation ID: 54516). For these reasons, this variant has been classified as Pathogenic. -
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:research
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Breast and/or ovarian cancerPathogenic:1
Jun 11, 2019
CZECANCA consortium
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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Carcinoma of pancreasPathogenic:1
Mar 04, 2021
CZECANCA consortium
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
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Malignant tumor of breastPathogenic:1
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Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
The BRCA1 p.Glu755* variant was identified in 7 of 1280 proband chromosomes (frequency: 0.005) from individuals or families with breast or ovarian cancer (Foretova 2004, Machackova 2008, Pohlreich 2005). The variant was also identified in dbSNP (ID: rs41286296) as "With Pathogenic, Uncertain significance allele", ClinVar (classified as pathogenic by ENIGMA, CIMBA, COGR and BIC), and in LOVD 3.0 (6x as pathogenic). The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2263G>T variant leads to a premature stop codon at position 755 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in BRCA1 associated cancers and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
The p.E755* pathogenic mutation (also known as c.2263G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 2263. This changes the amino acid from a glutamic acid to a stop codon within coding exon 9. This variant was reported in multiple individuals with features consistent with BRCA1-related hereditary breast and ovarian cancer syndrome (Ramus SJ et al. Am J Hum Genet, 1997 May;60:1242-6; Foretova L et al. Hum Mutat, 2004 Apr;23:397-8; Machackova E et al. BMC Cancer, 2008 May;8:140). Of note, this variant is also designated as 2382G>T in the published literature. 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. -