ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1168G>A (p.Asp390Asn) (rs147737737)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115369 SCV000149278 uncertain significance not specified 2017-04-28 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1168G>A at the cDNA level, p.Asp390Asn (D390N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAT>AAT). Terui et al. (2013) concluded that this variant had no impact on functionality of MSH6 based on a prediction model which included integration of in silico models and other structural properties. MSH6 Asp390Asn was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Asp390Asn occurs at a position where amino acids with properties similar to Aspartic Acid are tolerated across species and is located in domain I of the MutS domain (Terui 2013). In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. Based on the currently available information, we consider MSH6 Asp390Asn to be a variant of uncertain significance.
Invitae RCV000552028 SCV000624617 uncertain significance Hereditary nonpolyposis colon cancer 2018-06-08 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 390 of the MSH6 protein (p.Asp390Asn). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs147737737, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 127555). General algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD), and an algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggest that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies. 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 RCV000570684 SCV000669885 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000570684 SCV000690177 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-03 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000758608 SCV000887363 likely benign Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.1168G>A has a 1.8% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.

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