Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000076336 | SCV000107360 | uncertain significance | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Insufficient evidence |
| Invitae | RCV001308701 | SCV001498166 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2022-09-14 | criteria provided, single submitter | clinical testing | This variant is present in population databases (rs267607911, gnomAD 0.007%). This sequence change affects the initiator methionine of the MSH2 mRNA. The next in-frame methionine is located at codon 26. Disruption of the initiator codon has been observed in individual(s) with MSH2-related conditions (PMID: 9718327, 18033691, 23047549, 28944238). 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. Reports on variants that affect the MSH2 initiator codon, c.1A>C and c.1A>T, indicate that Met26 may serve as an alternate initiator codon (PMID: 21837758, 9718327, 18781192). An experimental study of a recombinant MSH2 protein lacking the first 25 amino acid residues has shown that the truncated protein remains partially functional (PMID: 21837758). The clinical significance of these findings is unknown. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 90834). Disruption of the initiator codon has been observed on the opposite chromosome (in trans) from a pathogenic variant in MSH2 in an individual who was not affected with recessive MSH2-related conditions (PMID: 18781192, 25639900). This suggests that this variant may not be disease-causing. |
| Ambry Genetics | RCV002415556 | SCV002721819 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-03-03 | criteria provided, single submitter | clinical testing | The p.M1? variant (also known as c.1A>T) is located in coding exon 1 of the MSH2 gene and results from a A to T substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). 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). Alterations at the initiation codon of MSH2 have been identified in several cancer cohorts including ovarian cancer, early-onset colorectal cancer (diagnosed under age 30) and known or suspected Lynch syndrome cases; however, tumors do not consistently demonstrate a pattern of MSI and mismatch repair protein-deficient IHC staining (Farrington SM et al. Am. J. Hum. Genet. 1998 Sep 63(3):749-59; Otway R et al. Hum. Mutat. 2000;16(1):61-7; Barnetson RA et al. N. Engl. J. Med. 2006 Jun;354(26):2751-63; Barnetson RA et al. Hum. Mutat. 2008 Mar;29(3):367-74; Pal T et al. Br. J. Cancer. 2012 Nov;107(10):1783-90; Desmond A et al. JAMA Oncol. 2015 Oct;1(7):943-51). Further, transfection of a similar alteration impacting the initiation codon of MSH2, c.1A>C, cDNA into an MSH2-null, human endometrial cancer cell line showed slight, but statistically significant decrease in repair of an exogenous mismatched protein. This attenuated effect may be due to partial function of the truncated protein and/or expression of the full-length protein resulting from weak translation at the altered, non-AUG start codon, which was detected concomitantly with the truncated protein in this study (Cyr JL et al. Mol. Carcinog. 2012 Aug;51(8):647-58). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear. |