Submissions for variant NM_000179.3(MSH6):c.753A>G (p.Ile251Met)

dbSNP: rs587779321

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506023	SCV000601618	uncertain significance	not specified	2016-12-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000803732	SCV000943616	benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001026537	SCV001188939	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-16	criteria provided, single submitter	clinical testing	The p.I251M variant (also known as c.753A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 753. The isoleucine at codon 251 is replaced by methionine, an amino acid with highly similar properties. 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. In addition, the CoDP in silico tool predicts this alteration to have a minor impact on molecular function, with a score of 0.000 (Terui H et al. J. Biomed. Sci. 2013 Apr;20:25). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001026537	SCV001350842	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 251 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 1/251174 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	RCV003997103	SCV004837008	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 251 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 1/251174 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.
GeneDx	RCV004767059	SCV005379702	uncertain significance	not provided	2023-11-25	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in the control group and absent in cases in a study of biliary tract cancer (PMID: 36243179); This variant is associated with the following publications: (PMID: 21437237, 36243179, 26333163)