ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1273G>A (p.Glu425Lys)

dbSNP: rs1064795063
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482294 SCV000570500 uncertain significance not provided 2016-05-31 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1273G>A at the cDNA level, p.Glu425Lys (E425K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Glu425Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Glu425Lys occurs at a position that is not conserved and is located in the Lever domain and the MSH6 and MSH3 interaction 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 Glu425Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV001010687 SCV001170920 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-28 criteria provided, single submitter clinical testing The p.E425K variant (also known as c.1273G>A), located in coding exon 7 of the MSH2 gene, results from a G to A substitution at nucleotide position 1273. The glutamic acid at codon 425 is replaced by lysine, an amino acid with similar properties. In a massively parallel cell-based functional assay testing susceptibility to a DNA damaging agent, 6-thioguanine (6-TG), this variant was reported to be functionally neutral (Jia X et al. Am J Hum Genet, 2021 01;108:163-175). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV001300622 SCV001489768 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-08-04 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. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33357406) indicates that this missense variant is not expected to disrupt MSH2 function. ClinVar contains an entry for this variant (Variation ID: 421330). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 425 of the MSH2 protein (p.Glu425Lys).

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