Submissions for variant NM_000179.3(MSH6):c.517C>G (p.Leu173Val)

dbSNP: rs1553411421

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000559263	SCV000624980	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2017-01-11	criteria provided, single submitter	clinical testing	In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH6-related disease. This sequence change replaces leucine with valine at codon 173 of the MSH6 protein (p.Leu173Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine.
Ambry Genetics	RCV000571252	SCV000662564	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-06	criteria provided, single submitter	clinical testing	The p.L173V variant (also known as c.517C>G), located in coding exon 3 of the MSH6 gene, results from a C to G substitution at nucleotide position 517. The leucine at codon 173 is replaced by valine, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000571252	SCV000913010	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 173 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 not been identified 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	RCV004003700	SCV004838829	uncertain significance	Lynch syndrome	2023-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 173 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 not been identified 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.