Submissions for variant NM_000179.3(MSH6):c.2955C>G (p.Phe985Leu)

dbSNP: rs63750942

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000774605	SCV000908406	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 985 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 been reported in an individual affected with colorectal whose tumor displayed loss of MSH2 and MSH6 proteins via immunohistochemistry (PMID: 17348456). 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.
Ambry Genetics	RCV000774605	SCV001178780	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-26	criteria provided, single submitter	clinical testing	The p.F985L variant (also known as c.2955C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2955. The phenylalanine at codon 985 is replaced by leucine, an amino acid with highly similar properties. This variant, designated as "ex4 Phe985Leu(C/G)" was identified in a Latvian colorectal cancer patient whose tumor showed absent MSH6 staining by immunohistochemistry; however, only a portion of the MSH6 gene was sequenced (Irmejs A et al. Anticancer Res.27:653-8). 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.
Invitae	RCV001055550	SCV001219948	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 985 of the MSH6 protein (p.Phe985Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colorectal cancer (PMID: 17348456). ClinVar contains an entry for this variant (Variation ID: 89325). 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.
All of Us Research Program, National Institutes of Health	RCV003997083	SCV004839056	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 985 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 been reported in an individual affected with colorectal whose tumor displayed loss of MSH2 and MSH6 proteins via immunohistochemistry (PMID: 17348456). 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.