ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1204C>A (p.Gln402Lys) (rs63751412)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115497 SCV000149406 uncertain significance not provided 2015-02-28 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1204C>A at the cDNA level, p.Gln402Lys (Q402K) at the protein level, and results in the change of a Glutamine to a Lysine (CAA>AAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gln402Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution and may affect protein integrity. MSH2 Gln402Lys occurs at a position that is well conserved across species and is located in the Lever domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Gln402Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000206195 SCV000260627 uncertain significance Hereditary nonpolyposis colon cancer 2018-06-03 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 402 of the MSH2 protein (p.Gln402Lys). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and lysine. This variant is present in population databases (rs63751412, 0.009%) but has not been reported in the literature. ClinVar contains an entry for this variant (Variation ID: 127628). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change with uncertain impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000574856 SCV000662267 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Counsyl RCV000663163 SCV000786321 uncertain significance Lynch syndrome I 2018-04-06 criteria provided, single submitter clinical testing

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