Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2657_2658del(p.Ser886CysfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,672 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. S886S) 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
?
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 17-43092872-CAG-C is Pathogenic according to our data. Variant chr17-43092872-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 54629.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092872-CAG-C is described in Lovd as [Pathogenic]. Variant chr17-43092872-CAG-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2
Pathogenic, reviewed by expert panel
curation
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)
Apr 22, 2016
Variant allele predicted to encode a truncated non-functional protein. -
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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Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Nov 27, 2022
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54629). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 10486320). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser886Cysfs*16) 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
The c.2657_2658delCT pathogenic mutation (also known as 2774delCT and 2776delCT), located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides between positions 2657 and 2658, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in a family with hereditary breast and ovarian cancer (Gayther SA, Am. J. Hum. Genet. 1999 Oct; 65(4):1021-9). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -