ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.175C>T (p.Pro59Ser)

gnomAD frequency: 0.00001  dbSNP: rs761033647
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482176 SCV000573059 uncertain significance not provided 2017-02-06 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.175C>T at the cDNA level, p.Pro59Ser (P59S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Pro59Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Pro59Ser occurs at a position that is not conserved and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH6 Pro59Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000557696 SCV000624690 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000560960 SCV000669892 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-11 criteria provided, single submitter clinical testing The p.P59S variant (also known as c.175C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 175. The proline at codon 59 is replaced by serine, an amino acid with similar properties. This amino acid position is 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.
Color Diagnostics, LLC DBA Color Health RCV000560960 SCV000903537 uncertain significance Hereditary cancer-predisposing syndrome 2023-10-05 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 59 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 not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 4/133738 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.
All of Us Research Program, National Institutes of Health RCV004003399 SCV004830403 uncertain significance Lynch syndrome 2024-01-11 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 59 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/133738 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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