Submissions for variant NM_000249.4(MLH1):c.2093C>T (p.Ser698Leu)

dbSNP: rs587778975

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478844	SCV000565169	uncertain significance	not provided	2015-01-02	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.2093C>T at the cDNA level, p.Ser698Leu (S698L) at the protein level, and results in the change of a Serine to a Leucine (TCA>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ser698Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ser698Leu occurs at a position that is highly conserved across mammals and is located in the region that interacts with PMS2/MLH3/PMS1 (Raevaara 2005). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Ser698Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001014407	SCV001175107	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-24	criteria provided, single submitter	clinical testing	The p.S698L variant (also known as c.2093C>T), located in coding exon 18 of the MLH1 gene, results from a C to T substitution at nucleotide position 2093. The serine at codon 698 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001014407	SCV001347596	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-02	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 698 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.
Invitae	RCV002525766	SCV002982983	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-01-17	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 418307). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 698 of the MLH1 protein (p.Ser698Leu).
All of Us Research Program, National Institutes of Health	RCV004002244	SCV004843277	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 698 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed 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.