Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
RCV000076649 | SCV000107684 | no known pathogenicity | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Multifactorial likelihood analysis posterior probability <0.001 |
Mendelics | RCV000986651 | SCV001135705 | benign | Lynch syndrome 1 | 2019-05-28 | criteria provided, single submitter | clinical testing | |
Color Diagnostics, |
RCV001524492 | SCV001734361 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-17 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with glycine at codon 198 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406). Another study demonstrated that this variant is resistant to methylation-inducted cell death and likely defective in mismatch-repair (PMID: 30998989). This variant has been reported in individuals affected with Lynch syndrome (PMID: 12702580), and it has been described that this variant segregates with disease (PMID: 12702580). However, multiple tumors show microsatellite stability (PMID: 17312306). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
Cancer Variant Interpretation Group UK, |
RCV002465508 | SCV002760190 | likely pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2021-10-08 | criteria provided, single submitter | curation | Data included in classification: Revel: 0.99 (PP3_sup) Absent from 118479 gnomAD v.2.1.1 non-cancer WES samples (PM2_mod) Jia et al., 2021, PMID: 33357406 – loss of function Bouvet (2019) PMID: 30998989: loss of function on methylation assay Protein expression/stability dramatically affected in yeast, 4% of WT Gammie et al., 2007, PMID: 17720936 Abolished interactions with MSH6, MSH3, MLH1, PMS1, EXO1 and POL30 in yeast two-hybrid assay proficient on yeast assay Martinez & Kolodner, 2010 PMID: 20176959 – 1.8% deficiency in Thr+ reversion assay, 0.2% deficiency in Lys+ assay & no significant change in Canr mutator assay (PS3_Str) Data not included in classification: 17 observations in LOVD Not seen in 2841 UK diagnostic tests No other clinically classified variants at codon. 4/6 missense variants at codon deleterious on Jia et al., 2021 assay |
All of Us Research Program, |
RCV000076649 | SCV004830761 | uncertain significance | Lynch syndrome | 2023-12-18 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with glycine at codon 198 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant impacts MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold >= 0.88, PMID: 33357406). Another study demonstrated that this variant is resistant to methylation-inducted cell death and likely defective in mismatch-repair (PMID: 30998989). This variant has been reported in individuals affected with Lynch syndrome (PMID: 12702580), and it has been described that this variant segregates with disease (PMID: 12702580). However, multiple tumors show microsatellite stability (PMID: 17312306). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional functional and clinical studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |