ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.726C>G (p.Asn242Lys) (rs748427458)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457050 SCV000548253 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 242 of the MSH2 protein (p.Asn242Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. 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. 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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.
GeneDx RCV000519119 SCV000618297 uncertain significance not provided 2017-02-22 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.726C>G at the cDNA level, p.Asn242Lys (N242K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAG). This variant has not, to our knowledge, been reported in the literature as pathogenic or benign. MSH2 Asn242Lys was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Asparagine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Asn242Lys occurs at a position that is conserved across species and is located in the connector domain (Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Asn242Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000775712 SCV000910129 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-03 criteria provided, single submitter clinical testing

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