Submissions for variant NM_000249.4(MLH1):c.1976G>C (p.Arg659Pro)

dbSNP: rs63749900

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075447	SCV000106445	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Abrogated function (MMR activity & aberrant splicing), >2 MSI-H tumours, co-segregation with disease & absent in 1000 genomes
Invitae	RCV001064800	SCV001229720	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2022-08-23	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects MLH1 function (PMID: 9697702, 10037723, 11793442, 12810663, 15864295, 16083711, 17510385). 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. ClinVar contains an entry for this variant (Variation ID: 89965). This missense change has been observed in individuals with Lynch syndrome (PMID: 8776590, 11555625, 11601928, 11793442, 16083711, 33191490). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 659 of the MLH1 protein (p.Arg659Pro).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237435	SCV002009367	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002415525	SCV002719004	pathogenic	Hereditary cancer-predisposing syndrome	2019-10-15	criteria provided, single submitter	clinical testing	The p.R659P pathogenic mutation (also known as c.1976G>C), located in coding exon 17 of the MLH1 gene, results from a G to C substitution at nucleotide position 1976. The arginine at codon 659 is replaced by proline, an amino acid with dissimilar properties. This alteration has been identified in individuals/families meeting Amsterdam criteria and demonstrating concordant tumor data with microsatellite instability and/or deficient protein expression of MLH1/PMS2 (Nyström-Lahti M et al. Genes Chromosomes Cancer. 1999 Dec;26:372-5; Nyström-Lahti M et al. Genes Chromosomes Cancer. 2002 Feb;33:160-7; Ambry internal data). This alteration was demonstrated to segregate with disease in eight affected relatives in one family (Nyström-Lahti M et al. Genes Chromosomes Cancer. 2002 Feb;33:160-7). Complementation assays demonstrated severely reduced MMR activity in cells transfected with this alteration (Takahashi M et al. Cancer Res. 2007 May;67:4595-604; Drost M et al. Hum. Mutat. 2010 Mar;31:247-53; Hinrichsen I et al. Clin. Cancer Res. 2013 May;19:2432-41) and severely reduced interaction with PMS2 (Guerrette S et al. J. Biol. Chem. 1999 Mar;274:6336-41; Kondo E et al. Cancer Res. 2003 Jun;63:3302-8; Andersen SD et al. Hum. Mutat. 2012 Dec;33:1647-55; Raevaara TE et al. Gastroenterology. 2005 Aug;129:537-49; Vo AT et al. EMBO Rep. 2005 May;6:438-44). Additionally, RT-PCR and minigene assays have demonstrated defective splicing (Lastella P et al. BMC Genomics. 2006 Sep;7:243; Nyström-Lahti M et al. Hum. Mol. Genet. 1996 Jun;5:763-9). This amino acid position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice acceptor site; however, direct evidence is unavailable. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, p.R659P is classified as a pathogenic mutation.
Myriad Genetics, Inc.	RCV003451088	SCV004187379	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-26	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 20020535, 23403630, 17510385]. This variant is expected to disrupt protein structure [Myriad internal data].