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

gnomAD frequency: 0.00001  dbSNP: rs863224635

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000195961	SCV000254357	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-12-30	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (internal data). 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.