Submissions for variant NM_000249.4(MLH1):c.1502T>G (p.Ile501Ser)

dbSNP: rs587780679

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122971	SCV000166245	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-05	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 501 of the MLH1 protein (p.Ile501Ser). 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: 29484706; Invitae). ClinVar contains an entry for this variant (Variation ID: 135847). 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.
Ambry Genetics	RCV000217500	SCV000277910	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-27	criteria provided, single submitter	clinical testing	The p.I501S variant (also known as c.1502T>G), located in coding exon 13 of the MLH1 gene, results from a T to G substitution at nucleotide position 1502. The isoleucine at codon 501 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in a patient affected with breast cancer (Guacci A et al. J Clin Lab Anal, 2018 Jul;32:e22418). 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.
GeneDx	RCV000486481	SCV000573032	uncertain significance	not provided	2018-10-29	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.1502T>G at the cDNA level, p.Ile501Ser (I501S) at the protein level, and results in the change of an Isoleucine to a Serine (ATT>AGT). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MLH1 Ile501Ser was not observed in large population cohorts (Lek 2016). This variant is located in the region of interaction with EXO1 as well as 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, it is unclear whether MLH1 Ile501Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000217500	SCV000689819	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with serine at codon 501 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with clinical features of Lynch syndrome (ClinVar SCV000166245.6) and an individual affected with breast cancer (PMID: 29484706). 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.
Counsyl	RCV000662470	SCV000784962	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-02-22	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662470	SCV004018140	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-14	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486481	SCV004220073	uncertain significance	not provided	2023-01-31	criteria provided, single submitter	clinical testing	It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with breast cancer (PMID: 29484706 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997400	SCV004841028	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with serine at codon 501 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with clinical features of Lynch syndrome (ClinVar SCV000166245.6) and an individual affected with breast cancer (PMID: 29484706). 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.