Submissions for variant NM_000249.4(MLH1):c.1676T>C (p.Leu559Pro)

dbSNP: rs63750059

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000204126	SCV000259172	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability 0.95-0.99
GeneDx	RCV000522242	SCV000618313	likely pathogenic	not provided	2018-06-18	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.1676T>C at the cDNA level, p.Leu559Pro (L559P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). This variant has been reported in an individual with MSI-H colon cancer from a family meeting Amsterdam II Lynch syndrome criteria (Hardt 2011). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) describes a family meeting Amsterdam I criteria and classifies this variant as likely pathogenic (Thompson 2014). MLH1 Leu559Pro was not observed in large population cohorts (Lek 2016). This variant is located in the regions of interaction with EXO1 and PMS2/MLH3/PMS1 (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider MLH1 Leu559Pro to be a likely pathogenic variant.
Invitae	RCV001853279	SCV002262167	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-08-03	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 559 of the MLH1 protein (p.Leu559Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 21404117). ClinVar contains an entry for this variant (Variation ID: 219290). 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 expected to disrupt MLH1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics	RCV002399757	SCV002714617	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-08-24	criteria provided, single submitter	clinical testing	The p.L559P variant (also known as c.1676T>C), located in coding exon 15 of the MLH1 gene, results from a T to C substitution at nucleotide position 1676. The leucine at codon 559 is replaced by proline, an amino acid with similar properties. This variant was identified in an individual with MSI-H colon cancer who met Amsterdam criteria II (Hardt K et al. Fam. Cancer, 2011 Jun;10:273-84). This alteration has been identified as somatic in conjunction with a somatic pathogenic MLH1 variant in one patient's tumor, as well as in conjunction with a germline pathogenic MLH1 variant in a second patient with a Lynch syndrome associated tumor. Both individuals' tumors demonstrated high microsatellite instability with loss of PMS2 and intact MLH1 expression by immunohistochemistry where MLH1 promotor hypermethylation was negative (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis . Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Myriad Genetics, Inc.	RCV003454536	SCV004189419	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-21	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [Myriad Internal Data]. This variant is expected to disrupt protein structure [Myriad internal data].