ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.607G>A (p.Gly203Arg) (rs587779973)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115536 SCV000149445 uncertain significance not provided 2017-08-03 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.607G>A at the cDNA level, p.Gly203Arg (G203R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>AGA). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in colorectal cancer (Yamada 2003). MSH2 Gly203Arg was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Gly203Arg occurs at a position that is not conserved and is located in the connector domain (L?tzen 2008, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Gly203Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000221014 SCV000275818 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000409174 SCV000489646 uncertain significance Lynch syndrome I 2016-11-02 criteria provided, single submitter clinical testing
Invitae RCV000472250 SCV000548295 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 203 of the MSH2 protein (p.Gly203Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs587779973, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 127647). 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: "Benign"; Align-GVGD: "Class C0"). An algorithm developed specifically for the MSH2 gene suggests that this missense change is likely to be tolerated (PMID: 18383312). These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, 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.
Color RCV000221014 SCV000685108 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-15 criteria provided, single submitter clinical testing

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