Submissions for variant NM_000179.3(MSH6):c.898C>T (p.Arg300Trp)

gnomAD frequency: 0.00001  dbSNP: rs779858670

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000220107	SCV000279482	uncertain significance	not provided	2018-11-09	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.898C>T at the cDNA level, p.Arg300Trp (R300W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Arg300Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the nuclear localization signals (Gassman 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Arg300Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000465049	SCV000551146	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566281	SCV000670096	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-16	criteria provided, single submitter	clinical testing	The p.R300W variant (also known as c.898C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 898. The arginine at codon 300 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000566281	SCV000685528	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 300 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been identified in 2/251284 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798725	SCV002042063	uncertain significance	Breast and/or ovarian cancer	2020-01-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002229338	SCV002511416	uncertain significance	not specified	2022-04-15	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.898C>T (p.Arg300Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251284 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.898C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000566281	SCV002536367	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-30	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003998626	SCV004834868	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 300 of the MSH6 protein. Computational prediction tool is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251284 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.