Submissions for variant NM_000249.4(MLH1):c.649C>A (p.Arg217Ser)

dbSNP: rs4986984

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000629821	SCV000750777	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 217 of the MLH1 protein (p.Arg217Ser). 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: 525659). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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	RCV002360496	SCV002658222	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-25	criteria provided, single submitter	clinical testing	The p.R217S variant (also known as c.649C>A), located in coding exon 8 of the MLH1 gene, results from a C to A substitution at nucleotide position 649. The arginine at codon 217 is replaced by serine, an amino acid with dissimilar properties. 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.
All of Us Research Program, National Institutes of Health	RCV004002775	SCV004835501	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with serine at codon 217 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 not been reported in individuals affected with MLH1-related disorders 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.
GenomeConnect - Invitae Patient Insights Network	RCV001535626	SCV001749652	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 10-02-2017 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.