ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1593A>C (p.Lys531Asn) (rs1553366599)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000581134 SCV000684949 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590460 SCV000696218 uncertain significance not provided 2016-06-28 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1593A>C (p.Lys531Asn) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). Lys531 is conserved in vertebrates, and is located in the DNA mismatch repair protein MutS clamp and core domains. However, functional nor structural studies had been published at the time of variant classification. This variant was absent in 121298 control chromosomes and has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
PreventionGenetics,PreventionGenetics RCV000590460 SCV000806003 uncertain significance not provided 2017-11-29 criteria provided, single submitter clinical testing
Invitae RCV000801092 SCV000940850 uncertain significance Hereditary nonpolyposis colon cancer 2018-07-30 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 531 of the MSH2 protein (p.Lys531Asn). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and asparagine. 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. ClinVar contains an entry for this variant (Variation ID: 489919). 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.

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