ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.2067G>C (p.Gln689His)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002589842 SCV002949639 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2022-09-06 criteria provided, single submitter clinical testing 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 MLH1 protein function. This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 689 of the MLH1 protein (p.Gln689His).
Ambry Genetics RCV003167458 SCV003858921 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-12 criteria provided, single submitter clinical testing The p.Q689H variant (also known as c.2067G>C), located in coding exon 18 of the MLH1 gene, results from a G to C substitution at nucleotide position 2067. The glutamine at codon 689 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. 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 RCV004007502 SCV004843266 uncertain significance Lynch syndrome 2023-05-30 criteria provided, single submitter clinical testing This missense variant replaces glutamine with histidine at codon 689 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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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