ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1660A>G (p.Ser554Gly)

dbSNP: rs63751656
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076214 SCV000107231 pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Variant causes splicing aberration leading to frameshift: full inactivation of variant allele
Ambry Genetics RCV000491028 SCV000580548 likely pathogenic Hereditary cancer-predisposing syndrome 2023-03-07 criteria provided, single submitter clinical testing The c.1660A>G variant (also known as p.S554G), located in coding exon 10 of the MSH2 gene, results from an A to G substitution at nucleotide position 1660. The serine at codon 554 is replaced by glycine, an amino acid with similar properties. In one study, this variant was detected in a colorectal cancer patient meeting Amsterdam I criteria whose tumor showed loss of MSH2 expression on immunohistochemistry (IHC) (Casey G et al. JAMA, 2005 Feb;293:799-809). This alteration has also been identified as germline as well as somatic in individuals whose Lynch syndrome-associated tumors displayed loss of MSH2 and/or MSH6 on IHC (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Conversion analysis performed in this study revealed c.1660A>G was associated with out-of-frame skipping of exon 10 (Casey G et al. JAMA, 2005 Feb;293:799-809). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985797 SCV001134343 uncertain significance not provided 2019-04-14 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV003452846 SCV004188171 pathogenic Lynch syndrome 1 2023-08-03 criteria provided, single submitter clinical testing This variant is considered pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 18561205].
Labcorp Genetics (formerly Invitae), Labcorp RCV003593895 SCV004293889 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-04-13 criteria provided, single submitter clinical testing 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. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (PMID: 15713769). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 90717). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15713769). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 554 of the MSH2 protein (p.Ser554Gly).

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