Submissions for variant NM_000179.3(MSH6):c.2963G>T (p.Arg988Leu)

dbSNP: rs115386788

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223636	SCV000273028	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	The p.R988L variant (also known as c.2963G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 2963. The arginine at codon 988 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000465720	SCV000551292	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000223636	SCV000685339	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-12	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with leucine at codon 988 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/243102 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589846	SCV000695834	uncertain significance	not provided	2016-07-11	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.2963G>T (p.Arg988Leu) 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). Arg988 is located in the core and clamp domains of the DNA mismatch repair protein Msh6 protein. However, this variant has not been evaluated for functional impact by in vivo/vitro studies. This variant was found in 4/113780 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0003906 (4/10240). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. It has not, to our knowledge, been reported in affected individuals via publications. In addition, one clinical diagnostic laboratory 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)-possibly benign until additional information becomes available.
Mendelics	RCV000708883	SCV000837905	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462404	SCV004195627	uncertain significance	Endometrial carcinoma	2023-08-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589846	SCV004221203	uncertain significance	not provided	2023-04-07	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00016 (4/24508 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32885271 (2021)) and male breast cancer (PMID: 30613976 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000589846	SCV001548840	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH6 p.Arg988Leu variant was identified in the literature, however the frequency of this variant in an affected population was not provided (Terui 2013). The variant was also identified in the following databases: dbSNP (ID: rs115386788) as "With Uncertain significance allele" and ClinVar/Clinvitae (2x, uncertain significance). The variant was not identified in the databases: Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in control databases in 4 of 243102 chromosomes at a frequency of 0.00002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg988 residue is conserved across most mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. One study predicted c.2963G>T as likely to be tolerated; this was through use of an algorithm developed specifically for MSH6 missense variants (Terui 2013). 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.