Submissions for variant NM_000179.3(MSH6):c.257C>T (p.Thr86Ile)

gnomAD frequency: 0.00002  dbSNP: rs768444916

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572033	SCV000664870	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-16	criteria provided, single submitter	clinical testing	The p.T86I variant (also known as c.257C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 257. The threonine at codon 86 is replaced by isoleucine, an amino acid with similar properties. This alteration has been previously identified in an individual from a North American cohort of individuals with early onset colon cancer. (Pearlman R et al. JAMA Oncol, 2017 Apr;3:464-471). This amino acid position is poorly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000629809	SCV000750765	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-13	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 86 of the MSH6 protein (p.Thr86Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colon cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 480918). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000572033	SCV000903779	likely benign	Hereditary cancer-predisposing syndrome	2016-01-12	criteria provided, single submitter	clinical testing
GeneDx	RCV001566523	SCV001790057	uncertain significance	not provided	2024-03-28	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; Observed in an individual with mismatch repair-proficient colon cancer (PMID: 27978560); This variant is associated with the following publications: (PMID: 31852831, 27978560)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001566523	SCV002046573	uncertain significance	not provided	2021-01-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265801	SCV002547886	uncertain significance	not specified	2022-05-23	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.257C>T (p.Thr86Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 44770 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.257C>T has been reported in the literature in an individual with MMR-proficient, early-onset colorectal cancer (Pearlman_2017) and glioblastoma (Vaubel_2020), however these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four laboratories classified the variant as VUS and one as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV003316740	SCV004017847	likely benign	Lynch syndrome 5	2023-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Baylor Genetics	RCV003465183	SCV004195707	uncertain significance	Endometrial carcinoma	2023-12-07	criteria provided, single submitter	clinical testing