Submissions for variant NM_000179.3(MSH6):c.2071C>T (p.Leu691Phe)

gnomAD frequency: 0.00001  dbSNP: rs765224443

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001014292	SCV001174986	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-22	criteria provided, single submitter	clinical testing	The p.L691F variant (also known as c.2071C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 2071. The leucine at codon 691 is replaced by phenylalanine, 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.
Invitae	RCV001061259	SCV001225995	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 691 of the MSH6 protein (p.Leu691Phe). This variant is present in population databases (rs765224443, gnomAD 0.0009%). 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: 820638). 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.
Color Diagnostics, LLC DBA Color Health	RCV001014292	SCV001352807	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 691 of the MSH6 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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	RCV001569098	SCV001793093	uncertain significance	not provided	2021-07-31	criteria provided, single submitter	clinical testing	Located in the critical connector domain (Warren 2007, Kansikas 2011) Not observed in large population cohorts (Lek 2016) In silico analysis supports that this missense variant has a deleterious effect on protein structure/function Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003467616	SCV004197691	uncertain significance	Endometrial carcinoma	2023-09-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004004531	SCV004843802	uncertain significance	Lynch syndrome	2023-07-13	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 691 of the MSH6 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.