ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3524C>G (p.Thr1175Ser) (rs369583604)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214931 SCV000278144 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-21 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000486443 SCV000566053 uncertain significance not provided 2015-03-25 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3524C>G at the cDNA level, p.Thr1175Ser (T1175S) at the protein level, and results in the change of a Threonine to a Serine (ACT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Thr1175Ser was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Threonine and Serine share similar properties, this is considered a conservative amino acid substitution. MSH6 Thr1175Ser occurs at a position that is conserved across species and is located in domain V of the MutS domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Thr1175Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Mendelics RCV000708890 SCV000837917 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Invitae RCV001066026 SCV001231019 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-03-02 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 1175 of the MSH6 protein (p.Thr1175Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 233711). An algorithm developed specifically for the MSH6 gene (PMID: 23621914), suggests that this missense change is likely to be deleterious. However, this prediction has not been confirmed by published functional studies and its clinical significance is uncertain. 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 RCV000214931 SCV001353079 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-02 criteria provided, single submitter clinical testing

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