Submissions for variant NM_000179.3(MSH6):c.3350G>T (p.Cys1117Phe)

gnomAD frequency: 0.00001  dbSNP: rs773245315

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000230242	SCV000283800	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-10-16	criteria provided, single submitter	clinical testing
GeneDx	RCV000487138	SCV000568034	uncertain significance	not provided	2015-09-21	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3350G>T at the cDNA level, p.Cys1117Phe (C1117F) at the protein level, and results in the change of a Cysteine to a Phenylalanine (TGT>TTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Cys1117Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Cys1117Phe occurs at a position that is conserved in mammals and is not located in a known functional domain (Kariola 2002, Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Cys1117Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000570386	SCV000662389	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-30	criteria provided, single submitter	clinical testing	The p.C1117F variant (also known as c.3350G>T), located in coding exon 5 of the MSH6 gene, results from a G to T substitution at nucleotide position 3350. The cysteine at codon 1117 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000487138	SCV002774649	uncertain significance	not provided	2022-04-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000570386	SCV004357715	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 1117 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/282794 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	RCV003998729	SCV004835054	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 1117 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/282794 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.