Submissions for variant NM_000179.3(MSH6):c.2258C>G (p.Ser753Cys)

gnomAD frequency: 0.00002  dbSNP: rs876660934

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219984	SCV000278752	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-05	criteria provided, single submitter	clinical testing	The p.S753C variant (also known as c.2258C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2258. The serine at codon 753 is replaced by cysteine, 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.
Invitae	RCV000473229	SCV000551273	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 753 of the MSH6 protein (p.Ser753Cys). This variant is not present in population databases (gnomAD no frequency). 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: 234218). 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	RCV000219984	SCV000685271	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 753 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 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000985831	SCV001134408	uncertain significance	not provided	2020-01-27	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000985831	SCV001250447	uncertain significance	not provided	2020-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000985831	SCV001780603	uncertain significance	not provided	2020-04-06	criteria provided, single submitter	clinical testing	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	RCV003463605	SCV004197594	uncertain significance	Endometrial carcinoma	2023-10-22	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998608	SCV004841905	uncertain significance	Lynch syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 753 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 performed for this variant. This variant has not 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). 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.