Submissions for variant NM_000179.3(MSH6):c.3256C>G (p.Pro1086Ala)

dbSNP: rs756108143

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226723	SCV000283796	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-05-09	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1086 of the MSH6 protein (p.Pro1086Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 237186). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000482939	SCV000569278	uncertain significance	not provided	2018-01-30	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3256C>G at the cDNA level, p.Pro1086Ala (P1086A) at the protein level, and results in the change of a Proline to an Alanine (CCC>GCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Pro1086Ala was not observed in large population cohorts (Lek 2016). MSH6 Pro1086Ala 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 Pro1086Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl	RCV000662522	SCV000785079	uncertain significance	Lynch syndrome 5	2017-04-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000774607	SCV000908413	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000774607	SCV002527993	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-01	criteria provided, single submitter	curation
Ambry Genetics	RCV000774607	SCV003908554	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-17	criteria provided, single submitter	clinical testing	The p.P1086A variant (also known as c.3256C>G), located in coding exon 5 of the MSH6 gene, results from a C to G substitution at nucleotide position 3256. The proline at codon 1086 is replaced by alanine, an amino acid with highly similar properties. This variant was identified in 2 of 1682 Brazilian patients referred for hereditary cancer panel testing (de Oliveira JM et al. Eur J Hum Genet, 2022 Jul;30:818-823). This amino acid position is not well conserved in available vertebrate species, and alanine is the reference amino acid in other primate and vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Myriad Genetics, Inc.	RCV000662522	SCV004018456	uncertain significance	Lynch syndrome 5	2023-03-27	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.