Submissions for variant NM_000179.3(MSH6):c.2555A>C (p.Lys852Thr)

dbSNP: rs1114167796

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491145	SCV000580368	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-12	criteria provided, single submitter	clinical testing	The c.2555A>C (p.K852T) alteration is located in exon 4 (coding exon 4) of the MSH6 gene. This alteration results from a A to C substitution at nucleotide position 2555, causing the lysine (K) at amino acid position 852 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Invitae	RCV000705526	SCV000834526	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-08-16	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 428435). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 852 of the MSH6 protein (p.Lys852Thr).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759134	SCV000888258	uncertain significance	not provided	2017-11-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491145	SCV000910484	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 852 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 1/249204 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.
GeneDx	RCV000759134	SCV002008336	uncertain significance	not provided	2021-01-08	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 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
All of Us Research Program, National Institutes of Health	RCV004003466	SCV004842648	uncertain significance	Lynch syndrome	2023-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with threonine at codon 852 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 1/249204 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.