ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.44C>T (p.Pro15Leu)

gnomAD frequency: 0.00001  dbSNP: rs869312800
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000210179 SCV000266211 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Invitae RCV000791386 SCV000283843 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-07-06 criteria provided, single submitter clinical testing This missense change has been observed in individual(s) with Lynch syndrome and lymphoma, thyroid cancer and breast cancer (PMID: 26845104, 28874130). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 224584). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 15 of the MSH6 protein (p.Pro15Leu).
Ambry Genetics RCV001022587 SCV001184341 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-17 criteria provided, single submitter clinical testing The p.P15L variant (also known as c.44C>T), located in coding exon 1 of the MSH6 gene, results from a C to T substitution at nucleotide position 44. The proline at codon 15 is replaced by leucine, an amino acid with similar properties. 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.
All of Us Research Program, National Institutes of Health RCV000210179 SCV004825494 uncertain significance Lynch syndrome 2023-10-27 criteria provided, single submitter clinical testing This missense variant replaces proline with leucine at codon 15 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 individuals affected with Lynch syndrome, lymphoma, thyroid and Ductal carcinoma in situ (PMID: 26845104, 28874130). 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.

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