ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1732G>A (p.Glu578Lys)

gnomAD frequency: 0.00001  dbSNP: rs863224635
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195961 SCV000254357 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 578 of the MLH1 protein (p.Glu578Lys). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with MLH1-related cancer (PMID: 31391288). ClinVar contains an entry for this variant (Variation ID: 216333). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (Invitae). 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.
Ambry Genetics RCV000570899 SCV000664833 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-01 criteria provided, single submitter clinical testing The p.E578K variant (also known as c.1732G>A) is located in coding exon 16 of the MLH1 gene. The glutamic acid at codon 578 is replaced by lysine, 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 deleterious 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 RCV000570899 SCV001351188 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-09 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 578 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 an unspecified cancer (PMID: 31391288). This variant has been identified in 1/251236 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.
GeneDx RCV002305460 SCV002599678 uncertain significance not provided 2022-11-02 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; In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 12799449, 20533529, 22753075)
All of Us Research Program, National Institutes of Health RCV003997008 SCV004843203 uncertain significance Lynch syndrome 2023-09-05 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 578 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 an unspecified cancer (PMID: 31391288). This variant has been identified in 1/251236 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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