ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.433A>G (p.Ile145Val) (rs876659264)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221599 SCV000275515 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-16 criteria provided, single submitter clinical testing The p.I145V variant (also known as c.433A>G), located in coding exon 3 of the MSH2 gene, results from an A to G substitution at nucleotide position 433. The isoleucine at codon 145 is replaced by valine, an amino acid with highly similar properties. A similar alteration at this position, p.I145M, has been reported in multiple individuals diagnosed with hereditary nonpolyposis colorectal cancer (HNPCC) (Parc Y et al. J Med Genet 2003; 40:208; Kariola R et al. Hum. Genet. 2003 Feb; 112(2):105-9; Piñol V et al. JAMA 2005 Apr; 293(16):1986-94), but has been shown to be non-pathogenic by several functional studies (Gammie AE et al. Genetics 2007 Oct;177(2):707-21; Kansikas M et al. Hum. Mutat. 2011 Jan;32(1):107-15). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. In addition, this alteration is predicted to be benign by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000465648 SCV000548200 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 145 of the MSH2 protein (p.Ile145Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 231613). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000483760 SCV000573440 uncertain significance not provided 2017-02-17 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.433A>G at the cDNA level, p.Ile145Val (I145V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Ile145Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH2 Ile145Val occurs at a position that is not conserved and is located in the connector domain (Lützen 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH2 Ile145Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000662917 SCV000785860 uncertain significance Lynch syndrome I 2017-12-19 criteria provided, single submitter clinical testing
Color RCV000221599 SCV000904859 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780457 SCV000917720 uncertain significance not specified 2018-11-30 criteria provided, single submitter clinical testing Variant summary: MSH2 c.433A>G (p.Ile145Val) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246238 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.433A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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