Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_007294.4(BRCA1):c.117T>A(p.Cys39*) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. C39C) 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]
BRCA1 Gene-Disease associations (from GenCC):
breast-ovarian cancer, familial, susceptibility to, 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
Our verdict: Pathogenic. The variant received 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 17-43115743-A-T is Pathogenic according to our data. Variant chr17-43115743-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 479243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Hereditary breast ovarian cancer syndromePathogenic:2
Oct 20, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
Variant summary: The BRCA1 c.117T>A (p.Cys39X) 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. This variant is absent in 245588 control chromosomes. The variant of interest has not, to our knowledge, been reported as a germline variant in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. However, another variant affecting the same codon, c.117_118delTG, and leading to the same change on the protein level, p. Cys39*, has been reported in multiple affected individuals in published reportes as causative variant and cited as "pathogenic" by reputable reputable databases/clinical diagnostic laboratorie. Taken together, this variant is classified as pathogenic. -
Jul 15, 2020
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing
For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). A different variant (c.117_118del) giving rise to the same protein effect observed here (p.Cys39*) has been determined to be pathogenic (PMID: 27062684). This suggests that this variant is also likely to be causative of disease. This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 479243). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys39*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. -
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group SPathogenic:1
The p.C39* pathogenic mutation (also known as c.117T>A), located in coding exon 2 of the BRCA1 gene, results from a T to A substitution at nucleotide position 117. This changes the amino acid from a cysteine to a stop codon within coding exon 2. One functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562:217-222). A different alteration resulting in the same stop codon (referred to as either c.117_118delTG or 236_237delTG) has been reported as pathogenic in a family with early onset female breast and ovarian cancers (Osorio A et al. Br. J. Cancer. 2000 Apr;82:1266-70; Díez O et al. Hum Mutat. 2003 Oct;22:301-12; Brown A et al. Sultan Qaboos Univ Med J. 2019 Nov;19:e324-e334). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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. -