Submissions for variant NM_001040108.2(MLH3):c.2638C>G (p.Leu880Val)

gnomAD frequency: 0.00010  dbSNP: rs201453923

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691461	SCV000819240	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 7	2023-10-09	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 880 of the MLH3 protein (p.Leu880Val). This variant is present in population databases (rs201453923, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with colorectal cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 570572). 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. 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003238179	SCV002011212	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002465755	SCV002743349	uncertain significance	not specified	2022-08-24	criteria provided, single submitter	clinical testing	The p.L880V variant (also known as c.2638C>G), located in coding exon 1 of the MLH3 gene, results from a C to G substitution at nucleotide position 2638. The leucine at codon 880 is replaced by valine, an amino acid with highly similar properties. This variant has been identified in an individual whose colon tumor was microsatellite stable and demonstrated normal mismatch repair protein expression by immunohistochemistry (IHC) (Raskin L et al. Oncotarget, 2017 Nov;8:93450-93463). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465755	SCV002760754	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003239293	SCV003936136	uncertain significance	Endometrial carcinoma	2023-07-05	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with valine at codon 880 of the MLH3 protein (p.Leu880Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs201453923, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 570572). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"). 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000691461	SCV004015241	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 7	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with valine at codon 880 of the MLH3 protein (p.Leu880Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs201453923, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This missense change has been observed in individual(s) with colorectal cancer (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 570572). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"). 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.
Neuberg Centre For Genomic Medicine, NCGM	RCV000691461	SCV005061066	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 7		criteria provided, single submitter	clinical testing	The observed missense variant c.2638C>G (p.Leu880Val) in MLH3 gene has been reported previously in individual(s) affected with MLH3-associated cancer (Raskin et al. 2017). This variant is present with an allele frequency of 0.02% in the gnomAD exomes database. This variant has been submitted to the ClinVar database as Uncertain Significance (multiple submissions). The amino acid change p.Leu880Val in MLH3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 880 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).