ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2260A>C (p.Thr754Pro)

gnomAD frequency: 0.00001  dbSNP: rs545057945
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160679 SCV000211294 uncertain significance not provided 2018-12-11 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2260A>C at the cDNA level, p.Thr754Pro (T754P) at the protein level, and results in the change of a Threonine to a Proline (ACT>CCT). This variant was observed in at least one individual diagnosed with breast cancer (Lu 2015). MSH6 Thr754Pro was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Thr754Pro is located in the Lever domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether MSH6 Thr754Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV000772630 SCV000905824 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-11 criteria provided, single submitter clinical testing This missense variant replaces threonine with proline at codon 754 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 breast cancer (PMID: 29684080). This variant has been identified in 2/251058 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.
Invitae RCV000821022 SCV000961761 benign Hereditary nonpolyposis colorectal neoplasms 2023-10-09 criteria provided, single submitter clinical testing
Ambry Genetics RCV000772630 SCV001175745 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-29 criteria provided, single submitter clinical testing The p.T754P variant (also known as c.2260A>C), located in coding exon 4 of the MSH6 gene, results from an A to C substitution at nucleotide position 2260. The threonine at codon 754 is replaced by proline, an amino acid with highly similar properties. In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet, 2018 04;14:e1007352). 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.
All of Us Research Program, National Institutes of Health RCV003998496 SCV004841916 uncertain significance Lynch syndrome 2023-10-23 criteria provided, single submitter clinical testing This missense variant replaces threonine with proline at codon 754 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 breast cancer (PMID: 29684080). This variant has been identified in 2/251058 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.

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