ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2005G>C (p.Gly669Arg)

dbSNP: rs63751668
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076346 SCV000107370 uncertain significance Lynch syndrome 1 2018-06-13 reviewed by expert panel curation Criteria changed for variants in last base of exon therefore downgrade classification
Labcorp Genetics (formerly Invitae), Labcorp RCV001300623 SCV001489769 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-08-05 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 669 of the MSH2 protein (p.Gly669Arg). This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 22371642; Invitae). 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. Variants that disrupt 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. An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be deleterious (PMID: 22290698). ClinVar contains an entry for this variant (Variation ID: 90844).

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