Submissions for variant NM_000179.3(MSH6):c.490C>T (p.His164Tyr)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002340689	SCV002645414	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-04	criteria provided, single submitter	clinical testing	The p.H164Y variant (also known as c.490C>T), located in coding exon 3 of the MSH6 gene, results from a C to T substitution at nucleotide position 490. The histidine at codon 164 is replaced by tyrosine, 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.
GeneDx	RCV003443038	SCV004168045	uncertain significance	not provided	2023-04-18	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: 33516942)
Invitae	RCV003759133	SCV004471841	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-06-16	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) 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: 1744033). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. This variant is present in population databases (rs568685193, gnomAD 0.003%). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 164 of the MSH6 protein (p.His164Tyr).
All of Us Research Program, National Institutes of Health	RCV004005679	SCV004829286	uncertain significance	Lynch syndrome	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with tyrosine at codon 164 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 MSH6-related disorders in the literature. This variant has been identified in 1/246186 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.