Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.2959A>T(p.Lys987*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 (★★★). 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 17-43092572-T-A is Pathogenic according to our data. Variant chr17-43092572-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 266322.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092572-T-A is described in Lovd as [Pathogenic]. Variant chr17-43092572-T-A is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2
Oct 18, 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. -
Oct 02, 2015
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
- -
not provided Pathogenic:1
May 26, 2021
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in an individual with breast cancer (Yildiz Tacar 2020); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 3078A>T; This variant is associated with the following publications: (PMID: 29446198, 32846166) -
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The p.K987* pathogenic mutation (also known as c.2959A>T), located in coding exon 9 of the BRCA1 gene, results from an A to T substitution at nucleotide position 2959. This changes the amino acid from a lysine to a stop codon within coding exon 9. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
Nov 13, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Variant summary: The BRCA1 c.2959A>T (p.Lys987X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 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 (e.g. p.Leu1086X, p.Gln1111X, p.Glu1134X, etc.). This variant is absent in 245952 control chromosomes (gnomAD). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Taken together, this variant is classified as likely pathogenic. -