ClinVar Miner

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

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Total submissions: 6
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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 2019-08-15 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, ExAC 0.009%). This variant has not been reported in the literature in individuals with MSH2-related conditions. 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 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.
Ambry Genetics RCV000574856 SCV000662267 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-30 criteria provided, single submitter clinical testing Insufficient evidence
Counsyl RCV000663163 SCV000786321 uncertain significance Lynch syndrome I 2018-04-06 criteria provided, single submitter clinical testing
Color RCV000574856 SCV001355751 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193851 SCV001362999 uncertain significance not specified 2019-04-09 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1204C>A (p.Gln402Lys) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 277114 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1204C>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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