Submissions for variant NM_000249.4(MLH1):c.1154G>C (p.Arg385Pro)

dbSNP: rs63750430

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001010014	SCV001170155	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-18	criteria provided, single submitter	clinical testing	The p.R385P variant (also known as c.1154G>C), located in coding exon 12 of the MLH1 gene, results from a G to C substitution at nucleotide position 1154. The arginine at codon 385 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported in an Italian individual with adenomatous polyps (1-5) and a family history of colon cancer (Genuardi M et al. Eur. J. Hum. Genet.;7:778-82). 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 available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001340221	SCV001534021	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-07-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 385 of the MLH1 protein (p.Arg385Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with adenomatous polyps and a family history of colorectal cancer (PMID: 10573010). ClinVar contains an entry for this variant (Variation ID: 89654). 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 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.
Baylor Genetics	RCV003466954	SCV004190659	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-08-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001535638	SCV004220058	uncertain significance	not provided	2023-03-08	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in an individual affected with intestinal polyps and had a family history of colorectal cancer (PMID: 10573010 (1999)). It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
GenomeConnect - Invitae Patient Insights Network	RCV001535638	SCV001749667	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 07-12-2017 by Myriad. 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.