Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001376823 | SCV001573996 | likely pathogenic | Hereditary breast ovarian cancer syndrome | 2020-02-27 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Trp1837 amino acid residue in BRCA1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 28324225, 11802209, 27741520, 8968102, 15689452, 20516115, 27802165, 16267036). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRCA1 protein function. Additionally, another variant causing the same amino acid change, c.5510G>C, has been reported to affect BRCA1 protein function (PMID: 30209399). This variant has not been reported in the literature in individuals with BRCA1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with serine at codon 1837 of the BRCA1 protein (p.Trp1837Ser). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and serine. |
| ARUP Laboratories, |
RCV003738058 | SCV004564529 | likely pathogenic | not provided | 2023-10-04 | criteria provided, single submitter | clinical testing | The BRCA1 c.5510_5511delinsCT; p.Trp1837Ser variant, to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 1065962). This variant is also absent from the Genome Aggregation Database, indicating it is not a common polymorphism. Another variant resulting in the same amino acid change (c.5510G>C; p.Trp1837Ser) has been reported in individuals with breast and/or ovarian cancer (Kechin 2023, Wang 2019), and computational analyses predict that the p.Trp1837Ser variant is deleterious (REVEL: 0.854). Additionally, other amino acid substitutions at this codon (Arg, Gly, Cys) have been reported in individuals with breast and/or ovarian cancer (Abkevich 2004, Tran 2022, Wan 2019). Based on available information, the c.5510_5511delinsCT; p.Trp1837Ser variant is considered to be likely pathogenic. References: Abkevich V et al. Analysis of missense variation in human BRCA1 in the context of interspecific sequence variation. J Med Genet. 2004 Jul;41(7):492-507. PMID: 15235020. Kechin A et al. A spectrum of BRCA1 and BRCA2 germline deleterious variants in ovarian cancer in Russia. Breast Cancer Res Treat. 2023 Jan;197(2):387-395. PMID: 36367610. Tran VT et al. Pathogenic Variant Profile of Hereditary Cancer Syndromes in a Vietnamese Cohort. Front Oncol. 2022 Jan 5;11:789659. PMID: 35070997. Wan Q et al. Clinical phenotypes combined with saturation genome editing identifying the pathogenicity of BRCA1 variants of uncertain significance in breast cancer. Fam Cancer. 2021 Apr;20(2):85-95. PMID: 32803532. Wang J et al. Germline mutation landscape of Chinese patients with familial breast/ovarian cancer in a panel of 22 susceptibility genes. Cancer Med. 2019 May;8(5):2074-2084. PMID: 30982232. |