Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.5211_5212del(p.Gly1738ArgfsTer91) variant causes a frameshift change. 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. R1737R) 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
?
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 17-43057116-CCT-C is Pathogenic according to our data. Variant chr17-43057116-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 531396.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-43057116-CCT-C is described in Lovd as [Pathogenic]. Variant chr17-43057116-CCT-C is described in Lovd as [Pathogenic].
This deletion of two nucleotides in BRCA1 is denoted c.5211_5212delAG at the cDNA level and p.Gly1738ArgfsX91 (G1738RfsX91) at the protein level. This variant would be defined as BRCA1 5330delAG or 5330_5331delAG using alternate nomenclature. The normal sequence, with the bases that are deleted in brackets, is TCAG[delAG]GAGA. The deletion causes a frameshift which changes a Glycine to an Arginine at codon 1738, and creates a premature stop codon at position 91 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.5211_5212delAG has been observed in at least one individual with breast cancer (Ng 2016). We consider this variant to be pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Dec 02, 2017
For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Arg1835*) that lies downstream of this variant has been determined to be pathogenic (PMID: 12393792, 11739404, 27553291, 8554067, 10486320). This suggests that deletion of this region of the BRCA1 protein is causative of disease. This variant has been reported in an individual affected with breast cancer (PMID: 26757417). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the BRCA1 gene (p.Gly1738Argfs*91). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 126 amino acids of the BRCA1 protein. -