ClinVar Miner

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

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Total submissions: 3
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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 2016-01-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,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.

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