ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.751G>A (p.Glu251Lys) (rs147389443)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236679 SCV000293853 uncertain significance not provided 2016-01-20 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.751G>A at the cDNA level, p.Glu251Lys (E251K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Glu251Lys was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Glu251Lys occurs at a position that is not conserved 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 Glu251Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000562875 SCV000676082 uncertain significance Hereditary cancer-predisposing syndrome 2016-05-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000562875 SCV000685126 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-23 criteria provided, single submitter clinical testing
Invitae RCV001040201 SCV001203762 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-01-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 251 of the MSH2 protein (p.Glu251Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs147389443, ExAC 0.002%). This variant has not been reported in the literature in individuals with MSH2-related conditions. ClinVar contains an entry for this variant (Variation ID: 246341). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; 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.

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