ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1364A>C (p.Asn455Thr) (rs200938360)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131161 SCV000186105 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-15 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000524107 SCV000254274 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces asparagine with threonine at codon 455 of the MSH6 protein (p.Asn455Thr). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and threonine. This variant is present in population databases (rs200938360, ExAC 0.01%). This variant has been reported in individuals affected with bladder cancer and head and neck squamous cell carcinoma (PMID: 26689913, 26845104). ClinVar contains an entry for this variant (Variation ID: 142181). 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000196009 SCV000266201 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000590712 SCV000279331 uncertain significance not provided 2018-03-01 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1364A>C at the cDNA level, p.Asn455Thr (N455T) at the protein level, and results in the change of an Asparagine to a Threonine (AAC>ACC). This variant was observed in at least one individual with bladder cancer who underwent multi-gene cancer panel testing as well as an individual with squamous cell carcinoma of the head/neck (Lu 2015, Shirts 2016). Additionally, this variant was observed in 1/571 individuals with atherosclerosis, with no specific information about cancer history (Johnston 2012). MSH6 Asn455Thr was observed at an allele frequency of 0.07% (7/9,842) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is located in the mismatch binding domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Asn455Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000409980 SCV000487795 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-11-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590712 SCV000695780 uncertain significance not provided 2016-06-27 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.1364A>C (p.Asn455Thr) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 6/122462 control chromosomes at a frequency of 0.000049, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS. 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.
Color RCV000131161 SCV000902843 likely benign Hereditary cancer-predisposing syndrome 2016-01-14 criteria provided, single submitter clinical testing

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