Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000574685 | SCV000661102 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-03-15 | criteria provided, single submitter | clinical testing | 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. |
| Fulgent Genetics, |
RCV000763400 | SCV000894126 | pathogenic | Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000780971 | SCV000918669 | pathogenic | Hereditary breast ovarian cancer syndrome | 2017-10-20 | criteria provided, single submitter | 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. |
| Invitae | RCV000780971 | SCV001590942 | pathogenic | Hereditary breast ovarian cancer syndrome | 2020-07-15 | criteria provided, single submitter | clinical testing | 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. This variant is not present in population databases (ExAC no frequency). 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). 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. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic. |
| Brotman Baty Institute, |
RCV001076589 | SCV001242369 | not provided | Breast-ovarian cancer, familial, susceptibility to, 1 | no assertion provided | in vitro |