Submissions for variant NM_000179.3(MSH6):c.1079G>T (p.Ser360Ile)

dbSNP: rs267608060

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000556830	SCV000624610	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-11-11	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: 89167). 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 serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 360 of the MSH6 protein (p.Ser360Ile).
Ambry Genetics	RCV000564946	SCV000670110	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-04	criteria provided, single submitter	clinical testing	The p.S360I variant (also known as c.1079G>T), located in coding exon 4 of the MSH6 gene, results from a G to T substitution at nucleotide position 1079. The serine at codon 360 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration was identified in a 35 year-old German patient meeting Bethesda criteria who was diagnosed with MSI-H colon cancer demonstrating loss of MSH2 and MSH6 proteins on immunohistochemistry staining (Steinke V et al. Eur. J. Hum. Genet. 2008 May;16:587-92). This amino acid position is not 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	RCV000564946	SCV000908370	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-07	criteria provided, single submitter	clinical testing	This missense variant replaces serine with isoleucine at codon 360 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 been reported in an individual affected with colorectal cancer (PMID: 18301448). 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.
All of Us Research Program, National Institutes of Health	RCV003997061	SCV004837658	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces serine with isoleucine at codon 360 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 been reported in an individual affected with colorectal cancer (PMID: 18301448). 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.