Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002429034 | SCV002742156 | uncertain significance | Hereditary cancer-predisposing syndrome | 2025-01-16 | criteria provided, single submitter | clinical testing | The p.E902K variant (also known as c.2704G>A), located in coding exon 16 of the MSH2 gene, results from a G to A substitution at nucleotide position 2704. The glutamic acid at codon 902 is replaced by lysine, an amino acid with similar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was determined 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. Based on the available evidence, the clinical significance of this variant remains unclear. |
| Labcorp Genetics |
RCV005098259 | SCV005780807 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-02-24 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 902 of the MSH2 protein (p.Glu902Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1794967). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function with a negative predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |
| Department of Pathology and Laboratory Medicine, |
RCV005356134 | SCV005921130 | uncertain significance | Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2 | 2022-06-29 | criteria provided, single submitter | clinical testing |