Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3895C>T(p.Gln1299Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,872 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. Q1299Q) has been classified as Likely benign. 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
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PVS1 - null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
PP5
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PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43091636-G-A is Pathogenic according to our data. Variant chr17-43091636-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55040.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091636-G-A is described in Lovd as [Pathogenic]. Variant chr17-43091636-G-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:5
Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Oct 18, 2023
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Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
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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. -
Likely pathogenic, criteria provided, single submitter
clinical testing
Counsyl
Oct 18, 2016
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Pathogenic, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Dec 23, 2003
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Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Sep 13, 2023
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55040). This premature translational stop signal has been observed in individual(s) with breast cancer, and ovarian cancer (PMID: 12204006). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln1299*) 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). -
Pathogenic, no assertion criteria provided
research
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Jan 31, 2014
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Pathogenic, criteria provided, single submitter
clinical testing
Department of Pathology and Molecular Medicine, Queen's University
Apr 20, 2017
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not provided Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Apr 17, 2017
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Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Nov 21, 2018
This variant is denoted BRCA1 c.3895C>T at the cDNA level and p.Gln1299Ter (Q1299X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also reported as BRCA1 4014C>T using alternate nomenclature, has been reported in several Korean families with breast and/or ovarian cancer (Kang 2002, Shin 2016, Choi 2018). Based on currently available evidence, we consider this variant to be pathogenic. -
The p.Q1299* pathogenic mutation (also known as c.3895C>T), is located in coding exon 9 of the BRCA1 gene. This alteration results from a C to T substitution at nucleotide position 3895. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been detected in numerous Korean breast and/ or ovarian cancer patients and/ or families (Kang HC et al. Hum Mutat. 2002;20(3):235, Park JS et al. Clin Breast Cancer. 2018 10;18:362-373.e1; Choi MC et al. J Gynecol Oncol. 2018 Jul;29:e43; Bang YJ et al. Cancer Res Treat. 2021 Oct;:). 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. -