Submissions for variant NM_000249.4(MLH1):c.380G>A (p.Arg127Lys)

dbSNP: rs63751595

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075682	SCV000106685	pathogenic	Lynch syndrome	2018-10-18	reviewed by expert panel	curation	Last base of exon; Aberrant Splicing
Ambry Genetics	RCV000221216	SCV000276915	pathogenic	Hereditary cancer-predisposing syndrome	2022-01-04	criteria provided, single submitter	clinical testing	The c.380G>A pathogenic mutation (also known as p.R127K), located in coding exon 4 of the MLH1 gene, results from a G to A substitution at nucleotide position 380. The amino acid change results in arginine to lysine at codon 127, an amino acid with highly similar properties. This variant has been identified in a proband that met Amsterdam I/II criteria for Lynch syndrome and their tumor demonstrated high microsatellite instability (Chubb D et al. J Clin Oncol, 2015 Feb;33:426-32). This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome (Ambry internal data; Scott RJ et al. Am. J. Hum. Genet., 2001 Jan;68:118-127). This variant has also been identified in several probands whose Lynch syndrome-associated tumor demonstrated loss of MLH1/PMS2 expression by immunohistochemistry (Ambry internal data; Niessen RC et al. Gut, 2006 Dec;55:1781-8; Tian W et al. Int J Cancer, 2019 09;145:1290-1298). This alteration has been identified as somatic in conjunction with MLH1 copy neutral loss of heterozygosity (CN-LOH) in MSI-H colon tumors with loss of MLH1/PMS2 expression by immunohistochemistry where MLH1 promotor hypermethylation was negative (Ambry internal data; Haraldsdottir S et al. Gastroenterology, 2014 Dec;147:1308-1316.e1). In a study that quantified tumor characteristics to assess pathogenicity for germline mismatch repair gene variants, this variant was reported in an individual(s) whose Lynch syndrome-associated tumor demonstrated loss of MLH1/PMS2 expression on immunohistochemistry (Ambry internal data; Li S et al. J. Med. Genet. 2020 Jan;57:62-69). This nucleotide position is highly conserved in available vertebrate species. This alteration occurs in the last base pair of coding exon 4, which makes it likely to have some effect on normal mRNA splicing. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000686990	SCV000814537	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2021-01-07	criteria provided, single submitter	clinical testing	This variant has been reported in several individuals and families affected with Lynch syndrome (PMID: 11112663, 16636019, 18625694, 25559809, 31054147, Invitae). ClinVar contains an entry for this variant (Variation ID: 90194). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with lysine at codon 127 of the MLH1 protein (p.Arg127Lys). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 4, which is part of the consensus splice site for this exon.
Myriad Genetics, Inc.	RCV003451142	SCV004189530	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-13	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 31784484,]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16636019, 25559809, 31054147].