Submissions for variant NM_000249.4(MLH1):c.1489C>T (p.Arg497Trp)

gnomAD frequency: 0.00005  dbSNP: rs200830026

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132432	SCV000187526	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-14	criteria provided, single submitter	clinical testing	The p.R497W variant (also known as c.1489C>T), located in coding exon 13 of the MLH1 gene, results from a C to T substitution at nucleotide position 1489. The arginine at codon 497 is replaced by tryptophan, 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000168002	SCV000218653	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-12-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000588886	SCV000569883	uncertain significance	not provided	2017-01-11	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.1489C>T at the cDNA level, p.Arg497Trp (R497W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Arg497Trp was not observed at a significant allele frequency in 1000 Genomes. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Arg497Trp occurs at a position where amino acids with properties similar to Arginine are tolerated across species and is located in the PMS2/PMS1 interaction domain and region of interaction with EXO1 (Pang 1997, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Arg497Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000132432	SCV000684750	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 497 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 MLH1-related disorders in the literature. This variant has been identified in 9/282892 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588886	SCV000696114	uncertain significance	not provided	2016-11-01	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.1489C>T (p.Arg497Trp) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&Go not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 3/121412 (1/40469), which does not exceed the estimated maximal expected allele frequency for a pathogenic MLH1 variant of 1/1407. The variant of interest has not, to our knowledge, been reported in affected individuals via publications, however, multiple clinical diagnostic laboratories cite the variant as "uncertain significance." Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Sema4, Sema4	RCV000132432	SCV002528656	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV003998147	SCV004841024	uncertain significance	Lynch syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 497 of the MLH1 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 9/282892 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
GenomeConnect - Invitae Patient Insights Network	RCV001535466	SCV001749387	not provided	Mismatch repair cancer syndrome 1; Colorectal cancer, hereditary nonpolyposis, type 2		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 10-30-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.