Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4339C>T(p.Gln1447*) 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 17-43082422-G-A is Pathogenic according to our data. Variant chr17-43082422-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55173.Status of the report is reviewed_by_expert_panel, 3 stars.
Breast-ovarian cancer, familial, susceptibility to, 1Pathogenic:6
May 29, 2002
Breast Cancer Information Core (BIC) (BRCA1)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
May 05, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
A known pathogenic mutation was detected in the BRCA1 gene (c.4339C>T). This sequence change creates a premature translational stop signal (p.Gln1447*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in gnomAD genomes. This variant has been observed in several individuals with hereditary breast and/or ovarian cancer (PMID: 17319787, 18489799, 21203900, 31409081). ClinVar contains an entry for this variant (Variation ID: 55173) with 7 submissions, all of which classify it as pathegenic, 3 stars and reviewd by an expert panel. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). Therefore, this variant has been classified as Pathogenic. -
Apr 14, 2021
Baylor Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
- -
Sep 08, 2016
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Significance:Pathogenic
Review Status:reviewed by expert panel
Collection Method:curation
Variant allele predicted to encode a truncated non-functional protein. -
Jun 25, 2009
Sharing Clinical Reports Project (SCRP)
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
Breast and/or ovarian cancerPathogenic:1
Jun 11, 2019
CZECANCA consortium
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:clinical testing
- -
not providedPathogenic:1
Feb 06, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
This nonsense variant causes the premature termination of BRCA1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in a family with hereditary breast and/or ovarian cancer (HBOC) (PMID: 17319787 (2007), 21203900 (2011)) and individuals and families with a high risk of HBOC (PMID: 29446198 (2018), 31409081 (2019)). Based on the available information, this variant is classified as pathogenic. -
This variant changes 1 nucleotide in exon 12 of the BRCA1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with hereditary breast and/or ovarian cancer (PMID: 17319787, 21203900, 31409081). 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. -
Hereditary breast ovarian cancer syndromePathogenic:1
May 29, 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.Gln1447*) 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 hereditary breast and/or ovarian cancer (PMID: 17319787, 18489799). ClinVar contains an entry for this variant (Variation ID: 55173). For these reasons, this variant has been classified as Pathogenic. -
Familial prostate cancerPathogenic:1
Oct 17, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Variant summary: BRCA1 c.4339C>T (p.Gln1447X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251344 control chromosomes. c.4339C>T has been reported in the literature in at-least one individual affected with Cancer (example, Rebbeck_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 29446198). Six 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. -