Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076546 | SCV000107575 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Multifactorial likelihood analysis posterior probability 0.95-0.99 |
| Ambry Genetics | RCV002433581 | SCV002748230 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-04-23 | criteria provided, single submitter | clinical testing | The p.L93F variant (also known as c.277C>T), located in coding exon 2 of the MSH2 gene, results from a C to T substitution at nucleotide position 277. The leucine at codon 93 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration is observed in two family members whose colorectal tumors demonstrated high microsatellite instability and loss of MSH2 expression on immunohistochemistry (IHC) (Baudi F et al. Cancer Lett, 2005 Jun;223:285-91). This alteration was also detected in 1/537 French families tested for Lynch syndrome (Bonadona V et al. JAMA, 2011 Jun;305:2304-10). 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 01;108:163-175). In an in vitro complementation assay, this variant was determined to show partially reduced MMR activity (Drost M et al. Genet Med, 2019 07;21:1486-1496). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Cancer Variant Interpretation Group UK, |
RCV002465507 | SCV002760189 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2021-10-08 | criteria provided, single submitter | curation | Data included in classification: Absent from 118479 gnomAD v.2.1.1 non-cancer WES samples (PM2_mod) Revel: 0.87 (PP3_sup) Baudi et al., 2005, PMID: 15896463 – 2 case family with colorectal cancer at 27 & 43, both tumours MSI high and with loss of MSH2 on IHC (PP4_mod) Jia et al., 2021, PMID: 33357406 – functional (BS3_str) Data not included in classification: Drost et al., 2019, PMID: 30504929 – uncertain (original assay)/benign (multiple repeats) Classification as likely pathogenic by expert group (InSiGHT, 3* review, June 2019) as mostly based on Baudi et al., 2005 cases Bonadona et al., 201,1 PMID: 21642682 – Lynch syndrome family – no variant level phenotype information 7 Observations in LOVD Not seen in 2841 UK diagnostic tests |