Submissions for variant NM_000249.4(MLH1):c.2221C>A (p.Leu741Met)

dbSNP: rs786203583

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166962	SCV000217783	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-22	criteria provided, single submitter	clinical testing	The p.L741M variant (also known as c.2221C>A), located in coding exon 19 of the MLH1 gene, results from a C to A substitution at nucleotide position 2221. The leucine at codon 741 is replaced by methionine, an amino acid with highly similar properties. This variant has been reported in a patient with ovarian cancer at age 46 and a family history of colorectal and other cancers (Ricci MT et al. Tumori, 2019 Aug;105:338-352). This amino acid position is highly 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.
GeneDx	RCV000215072	SCV000279864	uncertain significance	not provided	2016-02-05	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.2221C>A at the cDNA level, p.Leu741Met (L741M) at the protein level, and results in the change of a Leucine to a Methionine (CTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Leu741Met 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 Leucine and Methionine share similar properties, this is considered a conservative amino acid substitution. MLH1 Leu741Met occurs at a position that is conserved across species and is located within the Pms1p-interactive domain as well as the region of interaction with PMS2, MLH3, and 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 Leu741Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000560309	SCV000625135	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 741 of the MLH1 protein (p.Leu741Met). 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: 187247). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt MLH1 function with a negative predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000166962	SCV000689868	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-06	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 741 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 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.
CeGaT Center for Human Genetics Tuebingen	RCV000215072	SCV004704362	uncertain significance	not provided	2024-02-01	criteria provided, single submitter	clinical testing	MLH1: PM2
All of Us Research Program, National Institutes of Health	RCV003995546	SCV004843299	uncertain significance	Lynch syndrome	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with methionine at codon 741 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 been reported in an individual affected with ovarian cancer who had a family history of colorectal cancer (PMID: 31068090). 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.
Baylor Genetics	RCV004567323	SCV005058007	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-12-26	criteria provided, single submitter	clinical testing