Submissions for variant NM_000179.3(MSH6):c.3172G>C (p.Asp1058His)

dbSNP: rs863225404

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000501351	SCV000920457	likely pathogenic	Lynch syndrome	2018-10-18	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability > 0.95 (0.953)
Ambry Genetics	RCV000491378	SCV000580085	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-11-03	criteria provided, single submitter	clinical testing	The p.D1058H variant (also known as c.3172G>C), located in coding exon 4 of the MSH6 gene, results from a G to C substitution at nucleotide position 3172. The aspartic asid at codon 1058 is replaced by histidine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. In addition, p.D1058H has been identified in at least one individual whose endometrial tumor demonstrated high microsatellite instability and/or loss of MSH6 expression on immunohistochemistry (IHC) (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site. In addition, this amino acid position is highly conserved in available vertebrate species and, as a missense substitution, is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV001039124	SCV001202636	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid with histidine at codon 1058 of the MSH6 protein (p.Asp1058His). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and histidine. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 218057). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202089	SCV000257236	uncertain significance	not specified		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353871	SCV000592623	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Asp1058His variant was not identified in the literature nor was it identified in any of the following databases: dbSNP, HGMD, UMD, “Mismatch Repair Genes Variant Database”, “InSiGHT Colon Cancer Database”, “MMR Gene Unclassified Variants Database”, or COSMIC. The p.Asp1058 residue is conserved across mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM) suggest that the p.Asp1058His variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant occurs within the last three bases of the exon, a position that has been shown to be part of the splicing consensus sequence, and variants involving this position sometimes affect splicing. Four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) predict a greater than 10% difference in splicing; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as a variant of unknown significance.