Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4609C>T(p.Gln1537*) 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]
Verdict is Pathogenic. Variant got 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 17-43074397-G-A is Pathogenic according to our data. Variant chr17-43074397-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55237.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43074397-G-A is described in Lovd as [Pathogenic]. Variant chr17-43074397-G-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5
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. -
Feb 08, 2008
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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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
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Dec 23, 2003
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Dec 03, 2017
Genomic Research Center, Shahid Beheshti University of Medical Sciences
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Hereditary breast ovarian cancer syndrome Pathogenic:3
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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Oct 23, 2023
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.4609C>T (p.Gln1537*) variant in the BRCA1 gene is located on the exon 14 and introduces an early stop codon. It is predicted to result in an absent or disrupted protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 12920083, 27165220, 30078507). This variant is absent in the general population database, gnomAD. The variant is reported in ClinVar as pathogenic (ID: 55237) and reviewed by the expert panel. Truncating variants in the BRCA1 gene are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore, this variant is classified as pathogenic. -
Jan 15, 2025
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.Gln1537*) 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 and ovarian (PMID: 12920083, 27165220, 30078507). This variant is also known as p.Q1537X (c.4728C>T). ClinVar contains an entry for this variant (Variation ID: 55237). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:1Uncertain:1
May 24, 2018
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This variant is denoted BRCA1 c.4609C>T at the cDNA level and p.Gln1537Ter (Q1537X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously reported as c.4728C>T, has been observed in association with breast and/or ovarian cancer (Ozcelik 2003, Yassaee 2016) and is considered pathogenic. -
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Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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BRCA1-related cancer predisposition Pathogenic:1
Feb 08, 2024
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.4609C>T (p.Gln1537*) variant in the BRCA1 gene is located on the exon 14 and introduces an early stop codon. It is predicted to result in an absent or disrupted protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 12920083, 27165220, 30078507). This variant is absent in the general population database, gnomAD. The variant is reported in ClinVar as pathogenic (ID: 55237) and reviewed by the expert panel. Truncating variants in the BRCA1 gene are known to be pathogenic (PMID: 21989022, 17661172, 22762150). Therefore, this variant is classified as pathogenic. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.Q1537* pathogenic mutation (also known as c.4609C>T), located in coding exon 13 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4609. This changes the amino acid from a glutamine to a stop codon within coding exon 13. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This pathogenic mutation, designated as 4728C>T, has been reported in one individual diagnosed with invasive breast cancer (Ozcelik H et al. J Med Genet. 2003 Aug;40(8):e91). This mutation has also been identified in a patient of Iranian ethnicity with both a personal and family history of breast and/or ovarian cancers (Yassaee VR et al. Asian Pac J Cancer Prev. 2016;17(S3):149-53). 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. -