ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2005G>T (p.Gly669Cys) (rs63751668)

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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 RCV000566809 SCV000676071 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000566809 SCV000690038 likely pathogenic Hereditary cancer-predisposing syndrome 2018-10-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781556 SCV000919694 uncertain significance not specified 2018-03-28 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2005G>T (p.Gly669Cys) variant involves the alteration of a conserved last nucleotide of exon 12. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5 splicing donor site. If transcribed without splice alteration, the variant would result in a non-conservative amino acid change located in the loop region within Walker boxes in ATPase domain (domain V) in the encoded protein sequence, with five of five in-silico tools predicting damaging effect of the variant on protein function. However these predictions have yet to be confirmed by functional studies. The variant was absent in 243882 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2005G>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. However, a different variant affecting the same nucleotide position (c.2005G>C, p.Gly669Arg) was reported to be found in 2 LS patients who showed absent expression of MSH2 protein by immunohistochemistry; this report might indicate the importance of this nucleotide- or amino acid position (PMID: 22371642). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely pathogenic, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV001069626 SCV001234805 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with cysteine at codon 669 of the MSH2 protein (p.Gly669Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. This variant also falls at the last nucleotide of exon 12 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). This variant has been reported in an individual in the Universal Mutation Database (Unpublished data). ClinVar contains an entry for this variant (Variation ID: 486870). 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 and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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