Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076684 | SCV000107719 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Coding sequence variation resulting in a stop codon |
| Invitae | RCV001223404 | SCV001395553 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2019-06-22 | criteria provided, single submitter | clinical testing | This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser233Hisfs*22) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. This variant has been observed in an individual affected with Lynch syndrome (PMID: 11151427). ClinVar contains an entry for this variant (Variation ID: 11151427). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). |
| Ambry Genetics | RCV002362716 | SCV002664384 | pathogenic | Hereditary cancer-predisposing syndrome | 2019-06-14 | criteria provided, single submitter | clinical testing | The c.696_697delTT variant, located in coding exon 4 of the MSH2 gene, results from a deletion of two nucleotides at nucleotide positions 696 to 697, causing a translational frameshift with a predicted alternate stop codon (p.S233Hfs*22). This variant has been reported in a German male diagnosed with MSI-H colorectal cancer and kidney cancer (Pistorius SR et al. Int J Colorectal Dis, 2000 Nov;15:255-63). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. |
| Department of Pathology and Laboratory Medicine, |
RCV001358434 | SCV001554163 | pathogenic | Carcinoma of colon | no assertion criteria provided | clinical testing | The MSH2 p.Ser233HisfsX22 variant was identified in 2 of 4516 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch Syndrome (Mangold 2005, Bonadona 2011). The variant was also identified in dbSNP (ID: rs63750426) as "With Pathogenic allele", ClinVar and Clinvitae (as pathogenic by InSIGHT), UMD-LSDB (1x as Causal), Insight Colon Cancer Gene Variant Database (6x as pathogenic), and the Insight Hereditary Tumors Database (7x as pathogenic). The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was not identified in the control databases: 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Genome Aggregation Database (Feb 27, 2017) or the Exome Aggregation Consortium (August 8th 2016). The c.696_697del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 233 and leads to a premature stop codon 22 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the MSH2 gene are an established mechanism of disease in Lynch Syndrome and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. |