ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1945C>T (p.Pro649Ser)

gnomAD frequency: 0.00001  dbSNP: rs1280930048
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000688390 SCV000816000 benign Hereditary nonpolyposis colorectal neoplasms 2024-10-27 criteria provided, single submitter clinical testing
Ambry Genetics RCV001013801 SCV001174431 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-14 criteria provided, single submitter clinical testing The p.P649S variant (also known as c.1945C>T), located in coding exon 17 of the MLH1 gene, results from a C to T substitution at nucleotide position 1945. The proline at codon 649 is replaced by serine, an amino acid with similar properties. This amino acid position is not 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284502 SCV001470331 uncertain significance not provided 2019-10-09 criteria provided, single submitter clinical testing
GeneDx RCV001284502 SCV004168210 uncertain significance not provided 2023-05-10 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22949387, 22753075, 12799449, 20533529)
All of Us Research Program, National Institutes of Health RCV004004281 SCV004843243 uncertain significance Lynch syndrome 2023-11-02 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 649 of the MLH1 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 MLH1-related disorders in the literature. This variant has been identified in 1/251294 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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