Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492005 | SCV000580536 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-09-03 | criteria provided, single submitter | clinical testing | The c.1950dupT pathogenic mutation, located in coding exon 12 of the MSH2 gene, results from a duplication of T at nucleotide position 1950, causing a translational frameshift with a predicted alternate stop codon (p.I651Yfs*3). 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. |
| Invitae | RCV002523983 | SCV002963473 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2022-10-22 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 428506). This premature translational stop signal has been observed in individual(s) with family history of urinary tract cancer (PMID: 31615790). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ile651Tyrfs*3) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). |
| Myriad Genetics, |
RCV003449365 | SCV004187954 | pathogenic | Lynch syndrome 1 | 2023-08-04 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. |
| Laboratory for Molecular Medicine, |
RCV004017647 | SCV004848543 | likely pathogenic | Lynch syndrome | 2021-10-28 | criteria provided, single submitter | clinical testing | The p.Ile651TyrfsX3 variant in MSH2 has not been previously reported in individuals with Lynch syndrome and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 651 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the MSH2 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PM2_Supporting. |