Submissions for variant NM_000179.3(MSH6):c.3257C>T (p.Pro1086Leu)

gnomAD frequency: 0.00004  dbSNP: rs780345806

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000222192	SCV000279488	uncertain significance	not provided	2018-03-13	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3257C>T at the cDNA level, p.Pro1086Leu (P1086L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). This variant was observed in an individual with a personal history of a Lynch syndrome associated cancer or polyps (Yurgelun 2015). MSH6 Pro1086Leu was not observed in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Pro1086Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000536806	SCV000624838	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000562792	SCV000673930	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-19	criteria provided, single submitter	clinical testing	The p.P1086L variant (also known as c.3257C>T), located in coding exon 5 of the MSH6 gene, results from a C to T substitution at nucleotide position 3257. The proline at codon 1086 is replaced by leucine, an amino acid with similar properties. This alteration was identified in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174616	SCV001337818	uncertain significance	not specified	2020-01-14	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3257C>T (p.Pro1086Leu) results in a non-conservative amino acid change located in the core domain (IPR007696) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 31408 control chromosomes (i.e. 1/848 alleles in the Latino subpopulation in the gnomAD genomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3257C>T has been reported in the literature in an individual affected with Lynch syndrome-associated cancer or polyps (Yurgelun_2015). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000562792	SCV001349272	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1086 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754 ). This variant has been identified in 1/31408 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000222192	SCV002046672	uncertain significance	not provided	2021-02-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998628	SCV004835029	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 1086 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 been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754 ). This variant has been identified in 1/31408 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.