Submissions for variant NM_000249.4(MLH1):c.1935C>G (p.Asn645Lys)

dbSNP: rs863224636

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000196328	SCV000254363	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-22	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 645 of the MLH1 protein (p.Asn645Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 216335). 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 with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (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	RCV001013764	SCV001174391	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-11	criteria provided, single submitter	clinical testing	The p.N645K variant (also known as c.1935C>G), located in coding exon 17 of the MLH1 gene, results from a C to G substitution at nucleotide position 1935. The asparagine at codon 645 is replaced by lysine, an amino acid with 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.
Color Diagnostics, LLC DBA Color Health	RCV001013764	SCV001357338	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 645 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 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.
GeneDx	RCV002305461	SCV002599673	uncertain significance	not provided	2023-10-19	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; Identified via WES in an individual with a neurodevelopmental disorder and no personal history of cancer (Kraemer et al., 2019); This variant is associated with the following publications: (PMID: 31857677, 12799449, 20533529, 22753075, 31422574)
All of Us Research Program, National Institutes of Health	RCV003997010	SCV004843240	uncertain significance	Lynch syndrome	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 645 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 been reported as a secondary finding in a non-cancer study (PMID: 31422574). 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.