Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.3626T>G(p.Leu1209Ter) 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. L1209L) 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
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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
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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
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PP5 - Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 17-43091905-A-C is Pathogenic according to our data. Variant chr17-43091905-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 187637.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43091905-A-C is described in Lovd as [Pathogenic]. Variant chr17-43091905-A-C is described in Lovd as [Pathogenic].
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge
Oct 02, 2015
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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. -
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria provided
clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System
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The BRCA1 p.Leu1209X variant was not identified in the literature, nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), COSMIC, GeneInsight COGR, BIC or ARUP databases. The variant was identified in Clinvar database classified as Pathogenic by Ambry Genetics and in BRCA Share (UMD) 4x as causal. The variant was also identified in Fanconi Anemia Mutation Database (LOVD) 3x.The p.Leu1209X variant leads to a premature stop codon at position 1209, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
The p.L1209* pathogenic mutation (also known as c.3626T>G and 3745T>G), located in coding exon 9 of the BRCA1 gene, results from a T to G substitution at nucleotide position 3626. This changes the amino acid from a leucine to a stop codon within coding exon 9. Since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -