Submissions for variant NM_000179.3(MSH6):c.3299C>G (p.Thr1100Arg)

dbSNP: rs63750442

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129716	SCV000184519	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-18	criteria provided, single submitter	clinical testing	The p.T1100R variant (also known as c.3299C>G), located in coding exon 5 of the MSH6 gene, results from a C to G substitution at nucleotide position 3299. The threonine at codon 1100 is replaced by arginine, an amino acid with similar properties. This alteration was identified in a cohort of families from Sweden undergoing genetic testing for Lynch syndrome (Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36:2823-2835). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000222346	SCV000279714	uncertain significance	not provided	2019-08-15	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27601186, 23621914, 22863191)
Invitae	RCV001089139	SCV000551075	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129716	SCV000685384	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with arginine at codon 1100 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 been observed in a Lynch syndrome family (PMID: 27601186). In a large breast cancer case-control study, this variant has been reported in 4/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 26/282832 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	RCV000129716	SCV002528005	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-01	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003997519	SCV004835040	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with arginine at codon 1100 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 been observed in a Lynch syndrome family (PMID: 27601186). In a large breast cancer case-control study, this variant has been reported in 4/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 26/282832 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.