ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1076G>C (p.Arg359Thr) (rs63751604)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132158 SCV000187232 likely pathogenic Hereditary cancer-predisposing syndrome 2017-06-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000225952 SCV000284088 likely pathogenic Hereditary nonpolyposis colon cancer 2017-02-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 359 of the MSH2 protein (p.Arg359Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. It also falls at the last nucleotide of exon 6 of the MSH2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 142767). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Nucleotide substitutions at the last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. A different missense substitution at this codon (p.Arg359Ser) has been determined to be pathogenic (PMID: 17250665, 17720936, 18781619, 24362816). This suggests that the arginine residue is critical for MSH2 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this is a rare missense variant at the consensus splice site that is expected to affect mRNA splicing, and also affects a residue that is critical for MSH2 function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.