Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000804346 | SCV000944250 | uncertain significance | not provided | 2025-02-03 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 118 of the MSH3 protein (p.Asn118Ile). This variant is present in population databases (rs372970933, gnomAD 0.006%). This missense change has been observed in individual(s) with renal cancer (PMID: 38127826). ClinVar contains an entry for this variant (Variation ID: 649417). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The isoleucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. |
| Ambry Genetics | RCV001020555 | SCV001182050 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-09-14 | criteria provided, single submitter | clinical testing | The p.N118I variant (also known as c.353A>T), located in coding exon 2 of the MSH3 gene, results from an A to T substitution at nucleotide position 353. The asparagine at codon 118 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Baylor Genetics | RCV003461153 | SCV004196953 | uncertain significance | Endometrial carcinoma | 2024-03-28 | criteria provided, single submitter | clinical testing | |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000804346 | SCV004221104 | uncertain significance | not provided | 2024-11-05 | criteria provided, single submitter | clinical testing | The MSH3 c.353A>T (p.Asn118Ile) variant has been reported in the published literature in an individual with Huntington's Disease (PMID: 30358836 (2019)), as well as in a reportedly healthy individual in a melanoma study (PMID: 29641532 (2018)). The frequency of this variant in the general population, 0.000044 (5/113712 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. |
| Fulgent Genetics, |
RCV005047084 | SCV005673162 | uncertain significance | Endometrial carcinoma; Familial adenomatous polyposis 4 | 2024-06-11 | criteria provided, single submitter | clinical testing |