ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.743A>G (p.Lys248Arg) (rs1064794704)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000757471 SCV000569767 uncertain significance not provided 2016-03-30 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.743A>G at the cDNA level, p.Lys248Arg (K248R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Lys248Arg 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 Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. MSH2 Lys248Arg occurs at a position where amino acids with properties similar to Lysine are tolerated across species and is located in the connector domain (Lützen 2008). 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 Lys248Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757471 SCV000885712 uncertain significance not provided 2017-08-24 criteria provided, single submitter clinical testing The MSH2 c.743A>G; p.Lys248Arg variant (rs1064794704) has not been reported in the literature. It is listed in the ClinVar database (Variation ID: 420794), and is found in the general population with an overall allele frequency of 0.0004 percent (1/246214 alleles) in the Genome Aggregation Database. The lysine at codon 248 is moderately conserved, and computational programs (SIFT, PolyPhen2, Align GVGD) predict this variant to be tolerated. However, with the lack of information regarding p.Lys248Arg, its clinical significance is uncertain at this time. References: Link to ClinVar database for p.Lys248Arg:
Color RCV000775779 SCV000910226 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-23 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000757471 SCV001134373 uncertain significance not provided 2018-10-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000775779 SCV001188818 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-21 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV001046068 SCV001209953 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-10-03 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 248 of the MSH2 protein (p.Lys248Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 420794). 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 arginine 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.

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