Submissions for variant NM_000179.3(MSH6):c.3919A>C (p.Asn1307His)

dbSNP: rs730881808

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160700	SCV000211328	uncertain significance	not provided	2023-06-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 12019211, 17531815, 21120944)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000530579	SCV000624943	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-07-26	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with MSH6-related conditions. 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) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 182649). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 1307 of the MSH6 protein (p.Asn1307His).
Fulgent Genetics, Fulgent Genetics	RCV000764436	SCV000895493	uncertain significance	Endometrial carcinoma; Mismatch repair cancer syndrome 1; Lynch syndrome 5	2018-10-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001525984	SCV001736215	uncertain significance	Hereditary cancer-predisposing syndrome	2020-08-26	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 1307 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 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.
Ambry Genetics	RCV001525984	SCV002624092	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-05	criteria provided, single submitter	clinical testing	The p.N1307H variant (also known as c.3919A>C), located in coding exon 9 of the MSH6 gene, results from an A to C substitution at nucleotide position 3919. The asparagine at codon 1307 is replaced by histidine, an amino acid with similar properties. 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.
Baylor Genetics	RCV003467254	SCV004197667	uncertain significance	Endometrial carcinoma	2023-10-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160700	SCV004222022	uncertain significance	not provided	2022-10-18	criteria provided, single submitter	clinical testing	The variant has not been reported in individuals with MSH6-related conditions in the published literature. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003998505	SCV004835166	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with histidine at codon 1307 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 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.