ClinVar Miner

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

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000985821 SCV000149278 uncertain significance not provided 2020-05-14 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25224212, 26670666, 23621914)
Invitae RCV000552028 SCV000624617 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-09-09 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 conditions. ClinVar contains an entry for this variant (Variation ID: 127555). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). However, this prediction has not been confirmed by published functional studies and its 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 RCV000570684 SCV000669885 likely benign Hereditary cancer-predisposing syndrome 2018-11-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Structural Evidence
Color Health, Inc 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985821 SCV001134390 uncertain significance not provided 2019-07-11 criteria provided, single submitter clinical testing

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