Submissions for variant NM_000179.3(MSH6):c.3254C>T (p.Thr1085Ile)

dbSNP: rs761724581

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484206	SCV000569722	uncertain significance	not provided	2018-10-01	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3254C>T at the cDNA level, p.Thr1085Ile (T1085I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACC>ATC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Thr1085Ile was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Thr1085Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001019455	SCV001180816	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-08	criteria provided, single submitter	clinical testing	The p.T1085I variant (also known as c.3254C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3254. The threonine at codon 1085 is replaced by isoleucine, an amino acid with similar 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.
Color Diagnostics, LLC DBA Color Health	RCV001019455	SCV001348886	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-10	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1085 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 MSH6-related disorders in the literature. This variant has been identified in 1/249438 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.
Invitae	RCV001303106	SCV001492341	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-06-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003333	SCV004835022	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1085 of the MSH6 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <=0.5, 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 1/249438 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.