Submissions for variant NM_000179.3(MSH6):c.3524C>T (p.Thr1175Ile)

gnomAD frequency: 0.00002  dbSNP: rs369583604

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484936	SCV000572158	uncertain significance	not provided	2023-09-20	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 17531815, 21120944)
Ambry Genetics	RCV000573926	SCV000669934	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-07	criteria provided, single submitter	clinical testing	The p.T1175I variant (also known as c.3524C>T), located in coding exon 6 of the MSH6 gene, results from a C to T substitution at nucleotide position 3524. The threonine at codon 1175 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Invitae	RCV000706792	SCV000835862	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-09-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000573926	SCV001353080	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1175 of the MSH6 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/282662 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Sema4, Sema4	RCV000573926	SCV002528039	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-08	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004003383	SCV004835084	uncertain significance	Lynch syndrome	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 1175 of the MSH6 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/282662 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.