ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.566C>G (p.Ala189Gly) (rs141021599)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590509 SCV000211215 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.566C>G at the cDNA level, p.Ala189Gly (A189G) at the protein level, and results in the change of an Alanine to a Glycine (GCT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ala189Gly was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Alanine and Glycine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ala189Gly occurs at a position that is not conserved and is located within the connector domain (Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Ala189Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000233177 SCV000284173 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces alanine with glycine at codon 189 of the MSH2 protein (p.Ala189Gly). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and glycine. This variant is present in population databases (rs141021599, ExAC 0.003%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 182583). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Counsyl RCV000410808 SCV000489576 uncertain significance Lynch syndrome I 2016-10-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565216 SCV000662248 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-28 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000565216 SCV000685100 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001251062 SCV000696278 uncertain significance not specified 2020-07-15 criteria provided, single submitter clinical testing Variant summary: MSH2 c.566C>G (p.Ala189Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251470 control chromosomes (gnomAD). 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.566C>G in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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