Submissions for variant NM_000249.4(MLH1):c.545G>A (p.Arg182Lys)

dbSNP: rs587779021

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075753	SCV000106761	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant causes splicing aberration leading to truncated protein: full inactivation of variant allele
Labcorp Genetics (formerly Invitae), Labcorp	RCV001854303	SCV002130604	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2021-06-20	criteria provided, single submitter	clinical testing	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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing, but the impact on the resulting protein product is unknown (PMID: 26247049). 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 has been observed in individual(s) with colorectal cancer (PMID: 14635101). ClinVar contains an entry for this variant (Variation ID: 90264). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with lysine at codon 182 of the MLH1 protein (p.Arg182Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon.
Myriad Genetics, Inc.	RCV003452745	SCV004185683	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 26247049, Myriad internal data].
Ambry Genetics	RCV004943748	SCV005448472	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-09-06	criteria provided, single submitter	clinical testing	The c.545G>A variant (also known as p.R182K), located in coding exon 6 of the MLH1 gene, results from a G to A substitution at nucleotide position 545. The amino acid change results in arginine to lysine at codon 182, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. This variant has been identified in a probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability and/or loss of MLH1 and PMS2 expression by immunohistochemistry (Li S et al. J. Med. Genet. 2020 Jan;57:62-69; Carnevali IW et al. Genes (Basel), 2023 Nov; 14(11):2060; Ambry internal data).This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (van der Klift HM et al. Mol Genet Genomic Med, 2015 Jul;3:327-45). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.