Submissions for variant NM_000179.3(MSH6):c.1505T>C (p.Ile502Thr)

gnomAD frequency: 0.00003  dbSNP: rs749012012

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491991	SCV000580264	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-25	criteria provided, single submitter	clinical testing	The p.I502T variant (also known as c.1505T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 1505. The isoleucine at codon 502 is replaced by threonine, an amino acid with similar properties. This alteration was identified in a Japanese individual diagnosed with colorectal cancer (Terui H et al. Oncol Rep, 2013 Dec;30:2909-16). 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	RCV000523733	SCV000618391	uncertain significance	not provided	2019-01-14	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.1505T>C at the cDNA level, p.Ile502Thr (I502T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant has been reported in an individual with colorectal cancer whose tumor was shown to have microsatellite instability and absence of MLH1 and PMS2 proteins on mismatch repair immunohistochemistry; however, the tumor was also positive for MLH1 promoter hypermethylation (Terui 2013). MSH6 Ile502Thr was observed at an allele frequency of 0.02% (4/16512) in individuals of South Asian ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Ile502Thr occurs at a position that is not conserved and is located in the mismatch binding domain (Warren 2007, Kansikas 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Ile502Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000491991	SCV000908373	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-08	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 502 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, whose tumor showed microsatellite instability and absence of MLH1 and PMS2 proteins, as well as MLH1 promoter hypermethylation that could explain the observed phenotype (PMID: 24100870). This variant has been identified in 8/251198 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792665	SCV000931974	benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004806372	SCV005429275	uncertain significance	Lynch syndrome	2024-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 502 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, whose tumor showed microsatellite instability and absence of MLH1 and PMS2 proteins, as well as MLH1 promoter hypermethylation that could explain the observed phenotype (PMID: 24100870). This variant has been identified in 8/251198 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV005208137	SCV005849346	uncertain significance	Lynch syndrome 5	2023-06-22	criteria provided, single submitter	clinical testing	The missense c.1505T>C(p.Ile502Thr) variant in MSH6 gene has been reported previously in individual(s) affected with Colorectal cancer (Terui H, et al., 2013). The p.Ile502Thr variant is present with allele frequency of 0.003% in gnomAD Exomes. This variant has been reported to the ClinVar database as Benign / Uncertain Significance (multiple submissions). Multiple lines of computational evidences (Polyphen - Benign, SIFT - Tolerated and MutationTaster - Disease causing) predict conflicting evidence on protein structure and function for this variant. The reference amino acid at this position on MSH6 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ile at position 502 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).