ClinVar Miner

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

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132158 SCV000187232 likely pathogenic Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
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.
Integrated Genetics/Laboratory Corporation of America RCV001192615 SCV001360860 uncertain significance not specified 2019-07-05 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1076G>C (p.Arg359Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core (IPR007696) domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant falls at the last nucleotide of exon 6 of the MSH2 coding sequence, and therefore could impact splicing. Several computational tools predict significant effects on normal splicing: Five predict that the variant weakens a 5' donor site; one predicts that the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251388 control chromosomes. To our knowledge, no occurrence of c.1076G>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Because this variant is located within the splicing region of a critical domain, it is likely to result in an aberrant protein product. However, additional data is needed to conclusively determine the role of the variant in disease. Based on the evidence outlined above, the variant was classified as VUS possibly pathogenic.
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249911 SCV001423928 likely pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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