Submissions for variant NM_000249.4(MLH1):c.1811A>G (p.Lys604Arg)

dbSNP: rs1064795524

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000483140	SCV000571422	uncertain significance	not provided	2016-08-21	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.1811A>G at the cDNA level, p.Lys604Arg (K604R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Lys604Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. MLH1 Lys604Arg occurs at a position that is conserved across species and is located in the domain of interaction with PMS2/MLH3/PMS1 (Pang 1997, Raevaara 2005). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Lys604Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001013277	SCV001173845	uncertain significance	Hereditary cancer-predisposing syndrome	2019-01-24	criteria provided, single submitter	clinical testing	The p.K604R variant (also known as c.1811A>G), located in coding exon 16 of the MLH1 gene, results from an A to G substitution at nucleotide position 1811. The lysine at codon 604 is replaced by arginine, an amino acid with highly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003758790	SCV004447960	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 604 of the MLH1 protein (p.Lys604Arg). 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: 422053). 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. 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.
Baylor Genetics	RCV004568193	SCV005057961	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2024-03-13	criteria provided, single submitter	clinical testing