ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131161 SCV000186105 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-21 criteria provided, single submitter clinical testing The p.N455T variant (also known as c.1364A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 1364. The asparagine at codon 455 is replaced by threonine, an amino acid with similar properties. This alteration was described in individuals with bladder cancer, head and neck squamous cell carcinoma, and Cowden/Cowden-like (CS/CS-like) and Bannayan-Riley-Ruvalcaba syndromes (BRRS) without PTEN mutations (Shirts BH et al. Genet. Med., 2016 10;18:974-81; Lu C et al. Nat Commun, 2015 Dec;6:10086; Yehia L et al. PLoS Genet., 2018 04;14:e1007352). It was detected as a secondary finding in 1/571 patients ascertained for atherosclerosis phenotypes and in 1/345 individuals at high risk for pancreatic cancer who tested negative for germline mutations in pancreatic susceptibility genes (Johnston JJ et al. Am. J. Hum. Genet., 2012 Jul;91:97-108; Abe T et al. J. Clin. Oncol., 2019 05;37:1070-1080). It was also detected in 1/2512 control individuals from a healthy population database and in 0/165 colorectal cancer and/or polyposis patients (Rosenthal EA et al. Hum. Genet., 2018 Oct;137:795-806). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000524107 SCV000254274 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-28 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 2021-04-05 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with bladder, thyroid, and head and neck cancer (Lu 2015, Shirts 2016, Yehia 2018); This variant is associated with the following publications: (PMID: 26689913, 23621914, 22703879, 26845104, 28873162, 29684080)
Counsyl RCV000409980 SCV000487795 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-11-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Health, Inc RCV000131161 SCV000902843 likely benign Hereditary cancer-predisposing syndrome 2016-01-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590712 SCV001469566 uncertain significance not provided 2020-07-05 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355650 SCV001550593 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH6 p.Asn455Thr variant was identified in 1 of 1142 control chromosomes (frequency: 0.001) in individuals with atherosclerosis phenotypes undergoing secondary (incidental) variant detection by exome sequencing (Johnston 2012_ 22703879). A bioinformatic tool, CoDP ((Combination of the Different Properties), that integrates 3 prediction models (MAPP, PolyPhen-2 and SIFT) and 2 structural properties, found that the variant had no impact on the MSH6 protein (Terui 2013 23621914). The variant was also identified in dbSNP (ID: rs200938360) “With Uncertain significance allele”, ClinVar (as uncertain significance by Ambry Genetics, Invitae, University of Washington, GeneDx, and Counsyl), Clinvitae (4x as uncertain significance), LOVD 3.0 (1x), and in control databases in 13 of 245818 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1 of 15302 chromosomes (freq: 0.00007), Latino in 4 of 33544 chromosomes (freq: 0.0001), European Non-Finnish in 1 of 111452 chromosomes (freq: 0.000009), Ashkenazi Jewish in 7 of 9842 chromosomes (freq: 0.0007), while not observed in the Other, East Asian, European Finnish and South Asian populations. The variant was not identified in Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The p.Asn455 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Thr impacts the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.