Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.794_795delCT(p.Ser265CysfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S265S) 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
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 17-43094735-CAG-C is Pathogenic according to our data. Variant chr17-43094735-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 55707.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43094735-CAG-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3
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. -
Apr 20, 1998
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing
- -
Jul 01, 2015
Department of Medical Genetics, Oslo University Hospital
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
not provided Pathogenic:2
Jan 31, 2018
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This deletion of two nucleotides in BRCA1 is denoted c.794_795delCT at the cDNA level and p.Ser265CysfsX21 (S265CfsX21) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGTT[delCT]GTTT. The deletion causes a frameshift which changes a Serine to a Cysteine at codon 265, and creates a premature stop codon at position 21 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA1 c.794_795delCT, also defined as 913delCT using alternate nomenclature, has been observed in individuals with personal and/or family history of breast and/or ovarian cancer (Borg 1999, Heramb 2018). We consider this variant to be pathogenic. -
Mar 29, 2019
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data. -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The c.794_795delCT pathogenic mutation, located in coding exon 9 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 794 to 795, causing a translational frameshift with a predicted alternate stop codon (p.S265Cfs*21). This alteration was identified in a Norwegian individual diagnosed with ovarian cancer at 35 (Borg A et al. Dis. Markers, 1999 Oct;15:79-84). Additionally, in a large, clinic-based BRCA1/2 testing cohort in Norway, this variant was detected in 2 families (Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3). This alteration is also described in the literature as 913delCT. 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto