Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5084_5085del(p.Phe1695CysfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000684 in 1,461,774 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. F1695F) has been classified as Uncertain significance. 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
?
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
?
PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43063940-CAA-C is Pathogenic according to our data. Variant chr17-43063940-CAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 55388.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43063940-CAA-C is described in Lovd as [Pathogenic]. Variant chr17-43063940-CAA-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:3
Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
- -
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. -
Pathogenic, no assertion criteria provided
clinical testing
Breast Cancer Information Core (BIC) (BRCA1)
Dec 23, 2003
- -
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Feb 10, 2023
This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Phe1695Cysfs*3) 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 premature translational stop signal has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 21203900). ClinVar contains an entry for this variant (Variation ID: 55388). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Feb 24, 2020
Variant summary: BRCA1 c.5084_5085delTT (p.Phe1695CysfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 251232 control chromosomes (gnomAD). c.5084_5085delTT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Konecny_2011, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters, including one expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 (without evidence for independent evaluation), and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Neoplasm of ovary Pathogenic:1
Pathogenic, no assertion criteria provided
research
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne
Dec 01, 2018
- -
Breast neoplasm Pathogenic:1
Pathogenic, criteria provided, single submitter
research
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center
The c.5084_5085delTT pathogenic mutation, located in coding exon 16 of the BRCA1 gene, results from a deletion of two nucleotides at nucleotide positions 5084 to 5085, causing a translational frameshift with a predicted alternate stop codon (p.F1695Cfs*3). This mutation has been detected in multiple individuals diagnosed with breast and/or ovarian cancer (Konecny M et al, Breast Cancer Res. Treat. 2011 Feb; 126(1):119-30; Silva et al. BMC Med. Genet. 2014 May;15:55; Rebbeck et al. Hum. Mutat. 2018 05;39(5):593-620). Of note, this alteration is also designated as c.5084_5085del2 and c.5203delTT 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. -