Submissions for variant NM_000179.3(MSH6):c.1184C>T (p.Thr395Ile)

dbSNP: rs767658494

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210204	SCV000266200	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000481629	SCV000565213	uncertain significance	not provided	2017-02-24	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1184C>T at the cDNA level, p.Thr395Ile (T395I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant has been observed in at least one individual with skin cancer (Shirts 2016). MSH6 Thr395Ile was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Thr395Ile occurs at a position where amino acids with properties similar to Threonine are tolerated across species, and is located in the mismatch binding domain and nuclear localization signal domain (Warren 2007, Gassman 2011, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Thr395Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000491003	SCV000580242	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	clinical testing	The p.T395I variant (also known as c.1184C>T), located in coding exon 4 of the MSH6 gene, results from a C to T substitution at nucleotide position 1184. The threonine at codon 395 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000559226	SCV000624623	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 395 of the MSH6 protein (p.Thr395Ile). This variant is present in population databases (rs767658494, gnomAD 0.006%). This missense change has been observed in individual(s) with skin cancer or suspected Lynch syndrome (PMID: 26845104, 31391288). ClinVar contains an entry for this variant (Variation ID: 224579). 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.