Submissions for variant NM_000179.3(MSH6):c.1364A>C (p.Asn455Thr)

gnomAD frequency: 0.00004  dbSNP: rs200938360

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131161	SCV000186105	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-24	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	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-17	criteria provided, single submitter	clinical testing
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	2022-10-27	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with pancreatic, bladder, thyroid, and head and neck cancer (Lu et al., 2015; Shirts et al., 2016; Yehia et al., 2018; Abe et al., 2019); This variant is associated with the following publications: (PMID: 26689913, 23621914, 22703879, 26845104, 28873162, 29684080, 30883245, 21120944, 17531815)
Counsyl	RCV000409980	SCV000487795	uncertain significance	Lynch syndrome 5	2015-11-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281960	SCV000695780	uncertain significance	not specified	2023-08-11	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1364A>C (p.Asn455Thr) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6e-05 in 251056 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MSH6 causing Hereditary Nonpolyposis Colorectal Cancer (6e-05 vs 0.00014), allowing no conclusion about variant significance. c.1364A>C has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer or other type of cancer (examples: Shirts_2015, Lu_2015, Abe_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30883245, 22703879, 26689913, 26845104, 23621914). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=6) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	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	2023-07-31	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with head and neck squamous cell carcinoma (PMID: 26689913 (2015)), bladder cancer (PMID: 26845104 (2016)), pancreatic cancer (PMID: 30883245 (2019)), and thyroid cancer and melanoma (PMID: 32885271 (2021)). This variant has also been observed in an individual with no cancer history (PMID: 22703879 (2012)). The frequency of this variant in the general population, 0.00079 (8/10070 chromosomes in Ashkenazi Jewish subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000131161	SCV002535621	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-14	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409980	SCV004019018	likely benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
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.