Submissions for variant NM_000249.4(MLH1):c.86C>G (p.Ala29Gly)

dbSNP: rs63750216

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075896	SCV000106912	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberrations: full inactivation of variant allele. In-frame transcript interrupts ATPase domain.
Ambry Genetics	RCV000218998	SCV000276711	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-29	criteria provided, single submitter	clinical testing	The p.A29G pathogenic mutation (also known as c.86C>G), located in coding exon 1 of the MLH1 gene, results from a C to G substitution at nucleotide position 86. The alanine at codon 29 is replaced by glycine, an amino acid with similar properties.This pathogenic muation was reported in a Japanese family with Turcot syndrome where the 16 year old proband had been diagnosed with a glioblastoma. Authors showed that this mutation created a new cryptic splice donor site resulting in two transcripts of the MLH1 protein which were equally represented. One of the transcripts contained a frameshift leading to a premature stop codon, and the second transcript contained an in-frame deletion of 12 codons (Kanamori M et al. Oncogene. 2000 Mar 16;19(12):1564-71). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). This amino acid position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration creates a new and highly competitive cryptic donor splice site. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be borderline deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284650	SCV001470543	likely pathogenic	not provided	2020-08-13	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Myriad Genetics, Inc.	RCV003452780	SCV004185816	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-10	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 10734316].
Labcorp Genetics (formerly Invitae), Labcorp	RCV003593891	SCV004293445	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 29 of the MLH1 protein (p.Ala29Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 10734316, 21642682, 28514183, 34178123; Invitae). ClinVar contains an entry for this variant (Variation ID: 90403). 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. Studies have shown that this missense change is associated with altered splicing resulting in unknown protein product impact (Invitae). For these reasons, this variant has been classified as Pathogenic.