Submissions for variant NM_000179.3(MSH6):c.3703C>G (p.Leu1235Val)

gnomAD frequency: 0.00003  dbSNP: rs876661084

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000218152	SCV000279484	uncertain significance	not provided	2017-12-08	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3703C>G at the cDNA level, p.Leu1235Val (L1235V) at the protein level, and results in the change of a Leucine to a Valine (CTT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Leu1235Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Leucine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Leu1235Val is located in the ATPase domain (Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Leu1235Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000570599	SCV000662581	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-11	criteria provided, single submitter	clinical testing	The p.L1235V variant (also known as c.3703C>G), located in coding exon 8 of the MSH6 gene, results from a C to G substitution at nucleotide position 3703. The leucine at codon 1235 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV000570599	SCV000685431	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1235 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing. 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 4/282610 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000630095	SCV000751051	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1235 of the MSH6 protein (p.Leu1235Val). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 234558). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. 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.
All of Us Research Program, National Institutes of Health	RCV003998627	SCV004835115	uncertain significance	Lynch syndrome	2024-03-14	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1235 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may impact RNA splicing. 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 4/282610 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000218152	SCV001743469	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000218152	SCV001919361	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000218152	SCV001958997	uncertain significance	not provided		no assertion criteria provided	clinical testing