Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001858476 | SCV002236564 | uncertain significance | Fanconi anemia | 2023-10-09 | criteria provided, single submitter | clinical testing | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1805 of the SLX4 protein (p.Cys1805Arg). This variant is present in population databases (rs746191123, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 33558524). ClinVar contains an entry for this variant (Variation ID: 690302). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on SLX4 function (PMID: 23994477). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Fulgent Genetics, |
RCV002478944 | SCV002783585 | uncertain significance | Fanconi anemia complementation group P | 2022-05-04 | criteria provided, single submitter | clinical testing | |
| Center of Medical Genetics and Primary Health Care | RCV001005052 | SCV000987297 | uncertain significance | Hereditary breast cancer | 2020-05-01 | no assertion criteria provided | research | SLX4 missense variant p.Cys1805Arg is in exon 15 of the SLX4 gene in the structure-specific endonuclease subunit SLX4 domain (D1753-1810T aa). SLX4 is a regulatory subunit of the SLX1-SLX4 structure-specific endonuclease that resolves DNA secondary structures generated during DNA repair and recombination (Munoz et al., 2009; Fekairi et al., 2009). The allele frequency in GnomAD exomes is 0.000008 which does not exceed the estimated maximal expected allele frequency for a pathogenic SLX4 variant of 0.0001, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). 6 pathogenic predictions from DEOGEN2, FATHMM-MKL, M-CAP, MutationAssessor, MutationTaster and SIFT vs 5 benign predictions from DANN, EIGEN, MVP, PrimateAI and REVEL support its deleterious effect (PP3 Pathogenic Supporting). In our study this variant was found in two unrelated female patients with unilateral breast cancer- a 45-year-old patient with a strong family history of breast cancer and a 26-year-old patient with no reported family history of cancer. Based on the limited evidence and the fact that this variant has not been reported before in disease, we consider this variant as a Variant of Uncertain Significance. |