ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3299C>G (p.Thr1100Arg) (rs63750442)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129716 SCV000184519 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-28 criteria provided, single submitter clinical testing The p.T1100R variant (also known as c.3299C>G), located in coding exon 5 of the MSH6 gene, results from a C to G substitution at nucleotide position 3299. The threonine at codon 1100 is replaced by arginine, an amino acid with similar properties. This alteration was identified in a cohort of families from Sweden undergoing genetic testing for Lynch syndrome (Lagerstedt-Robinson K et al. Oncol. Rep. 2016 Nov;36:2823-2835). This amino acid position is 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.
GeneDx RCV000222346 SCV000279714 uncertain significance not provided 2017-06-28 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3299C>G at the cDNA level, p.Thr1100Arg (T1100R) at the protein level, and results in the change of a Threonine to an Arginine (ACG>AGG). This variant has been reported on at least one individual suspected to have Lynch syndrome (Lagerstedt-Robinson 2017). MSH6 Thr1100Arg was observed at an allele frequency of 0.136% (9/6614) in individuals of European (Finnish) ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Thr1100Arg occurs at a position where amino acids with properties similar to Threonine are tolerated across species and is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Thr1100Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV001089139 SCV000551075 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000129716 SCV000685384 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-30 criteria provided, single submitter clinical testing

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