ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.2033A>G (p.Lys678Arg)

dbSNP: rs1559592677
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000695670 SCV000824184 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-03-27 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 678 of the MLH1 protein (p.Lys678Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Sema4, Sema4 RCV002257936 SCV002528704 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-15 criteria provided, single submitter curation
Ambry Genetics RCV002257936 SCV002718726 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-16 criteria provided, single submitter clinical testing The p.K678R variant (also known as c.2033A>G), located in coding exon 18 of the MLH1 gene, results from an A to G substitution at nucleotide position 2033. The lysine at codon 678 is replaced by arginine, an amino acid with highly 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 RCV003999640 SCV004843255 uncertain significance Lynch syndrome 2023-03-23 criteria provided, single submitter clinical testing This missense variant replaces lysine with arginine at codon 678 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 been reported in an individual affected with early onset colorectal cancer (PMID: 28944238). 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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