Submissions for variant NM_000179.3(MSH6):c.1325T>C (p.Ile442Thr)

gnomAD frequency: 0.00001  dbSNP: rs587779210

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000627712	SCV000259234	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-08-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000213558	SCV000279377	uncertain significance	not provided	2019-06-24	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23621914, 26333163, 27701467)
Ambry Genetics	RCV000568557	SCV000662386	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-01	criteria provided, single submitter	clinical testing	The p.I442T variant (also known as c.1325T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 1325. The isoleucine at codon 442 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a cohort of 140 Japanese prostate cancer patients (Hayano T et al. PLoS ONE, 2016 Oct;11:e0164233). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000568557	SCV001356083	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 442 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 prostate cancer (PMID: 27701467). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 4/251114 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.
Sema4, Sema4	RCV000568557	SCV002535617	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-08	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003997065	SCV004841261	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 442 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 prostate cancer (PMID: 27701467). In a large breast cancer case-control study, this variant has been reported in 1/60466 cases and 2/53461 unaffected controls (PMID: 33471991). This variant has been identified in 4/251114 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.