Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2561_2562insGC(p.Gln855LeufsTer39) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,104 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. A854A) 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 17-43092969-A-AGC is Pathogenic according to our data. Variant chr17-43092969-A-AGC is described in ClinVar as [Pathogenic]. Clinvar id is 54600.Status of the report is reviewed_by_expert_panel, 3 stars.
The c.2560_2561dupGC pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a duplication of GC at nucleotide position 2560, causing a translational frameshift with a predicted alternate stop codon (p.Q855Lfs*39). This mutation has been reported in the literature in multiple individuals with personal and or family history consistent with hereditary breast and ovarian cancer syndrome (Robertson L et al, Br. J. Cancer 2012 Mar; 106(6):1234-8; Risch HA et al, J. Natl. Cancer Inst. 2006 Dec; 98(23):1694-706; Wilson BT et al, J Gynecol Oncol 2015 Oct; 26(4):249-51; Zhang S et al, Gynecol. Oncol. 2011 May; 121(2):353-7). Of note, this alteration is also designated as 2679_2680dupGC, 2680insGC, 2681insGC and 2561dupGC in published literature. 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. -
Pathogenic, criteria provided, single submitter
clinical testing
Color Diagnostics, LLC DBA Color Health
Sep 29, 2021
This variant inserts 2 nucleotides in exon 10 of the BRCA1 gene, creating a frameshift and 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 at least three individuals affected with breast cancer, ovarian cancer or breast and uterine cancer (PMID: 21324516, 22333603, 26404129, 33471991; Leiden Open Variation Database DB-ID BRCA1_003934). 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 syndrome Pathogenic:2
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
Invitae
Nov 12, 2023
This sequence change creates a premature translational stop signal (p.Gln855Leufs*39) 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/or ovarian cancer (PMID: 17148771, 22333603). This variant is also known as 2681insGC or c.2561dupGC. ClinVar contains an entry for this variant (Variation ID: 54600). For these reasons, this variant has been classified as Pathogenic. -