Submissions for variant NM_000179.3(MSH6):c.2963G>A (p.Arg988His)

dbSNP: rs115386788

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000214813	SCV000279452	uncertain significance	not provided	2020-10-26	criteria provided, single submitter	clinical testing	Has not been previously published as a germline pathogenic or benign variant to our knowledge; 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: 28912153, 30798936)
Invitae	RCV000534216	SCV000624806	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566696	SCV000669956	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	The p.R988H variant (also known as c.2963G>A), located in coding exon 4 of the MSH6 gene, results from a G to A substitution at nucleotide position 2963. The arginine at codon 988 is replaced by histidine, an amino acid with highly similar properties. This variant was also observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is not well conserved in available vertebrate species, and histidine is the reference amino acid in other 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.
Color Diagnostics, LLC DBA Color Health	RCV000566696	SCV000904024	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 988 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with endometrial cancer (PMID: 32885271). This variant has been identified in 11/217126 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.
All of Us Research Program, National Institutes of Health	RCV003998623	SCV004839111	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 988 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 11/217126 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354499	SCV001549132	uncertain significance	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH6 p.Arg988His variant was not identified in the literature nor was it identified in the COGR, MutDB, UMD-LSDB, Zhejiang University Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors database. The variant was identified in dbSNP (ID: rs115386788) as "With Uncertain significance allele”, ClinVar (classified as uncertain significance by Invitae, GeneDx and Ambry Genetics), and in Cosmic (1x in prostate tissue) database. The variant was identified in 11 of 212122 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 14826 chromosomes (freq: 0.00007), European in 1 of 99952 chromosomes (freq: 0.00001), and South Asian in 9 of 22466 chromosomes (freq: 0.0004); it was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Arg988 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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) 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.