Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000809239 | SCV000949382 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2020-12-15 | criteria provided, single submitter | clinical testing | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in a family affected with Lynch syndrome  (PMID: 18566915). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 618 of the MSH2 protein (p.Pro618Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. |
Ambry Genetics | RCV002406815 | SCV002717142 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-09-21 | criteria provided, single submitter | clinical testing | The p.P618S variant (also known as c.1852C>T), located in coding exon 12 of the MSH2 gene, results from a C to T substitution at nucleotide position 1852. The proline at codon 618 is replaced by serine, an amino acid with similar properties. This variant was identified amongst a Danish cohort with personal and/or family histories with variable suspicion of hereditary colon cancer (Nilbert M et al. Fam Cancer, 2009 Jun;8:75-83). In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 Jan;108:163-175). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |