Submissions for variant NM_000179.3(MSH6):c.3850A>G (p.Thr1284Ala)

dbSNP: rs1114167743

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491805	SCV000580238	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-19	criteria provided, single submitter	clinical testing	The p.T1284A variant (also known as c.3850A>G), located in coding exon 9 of the MSH6 gene, results from an A to G substitution at nucleotide position 3850. The threonine at codon 1284 is replaced by alanine, an amino acid with similar properties. This variant has been detected in conjunction with a pathogenic MLH1 alteration in a patient diagnosed with MSI-H colorectal cancer at age 34 (Yurgelun MB et al. J Clin Oncol. 2017 Apr 1;35(10):1086-1095). This amino acid position is highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001220225	SCV001392204	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-07-20	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 428360). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 28135145). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1284 of the MSH6 protein (p.Thr1284Ala).
Baylor Genetics	RCV003464050	SCV004195533	uncertain significance	Endometrial carcinoma	2023-09-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV004003457	SCV004818859	uncertain significance	Lynch syndrome	2023-03-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 1284 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, 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: 28135145), however, this individual also carried a pathogenic variant in the MLH1 gene that could explain the observed phenotype. 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.