Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.4981G>T(p.Glu1661Ter) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. E1661E) 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 17-43070933-C-A is Pathogenic according to our data. Variant chr17-43070933-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 55338.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43070933-C-A is described in Lovd as [Pathogenic]. Variant chr17-43070933-C-A is described in Lovd as [Pathogenic].
The p.E1661* pathogenic mutation (also known as c.4981G>T), located in coding exon 14 of the BRCA1 gene, results from a G to T substitution at nucleotide position 4981. This changes the amino acid from a glutamic acid to a stop codon within coding exon 14. This mutation was identified in multiple Korean patients with breast and ovarian cancer (Kang E et al. Breast Cancer Res. Treat., 2015 May;151:157-68; Choi DH et al. J. Clin. Oncol., 2004 May;22:1638-45; Kim H et al. Breast Cancer Res. Treat., 2012 Aug;134:1315-26; Ahn SH et al. Cancer Lett., 2007 Jan;245:90-5). 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
Pathogenic, criteria provided, single submitter
clinical testing
Invitae
Jan 11, 2024
This sequence change creates a premature translational stop signal (p.Glu1661*) 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: 15117986, 30309222). ClinVar contains an entry for this variant (Variation ID: 55338). For these reasons, this variant has been classified as Pathogenic. -