Submissions for variant NM_000249.4(MLH1):c.210AGA[1] (p.Glu71del)

dbSNP: rs63751642

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075552	SCV000106545	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Variant allele causes in-frame splicing aberration interrupting ATPase domain: full inactivation of variant allele
Ambry Genetics	RCV000565355	SCV000669512	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	clinical testing	The c.213_215delAGA pathogenic mutation (also known as p.E71del) is located in coding exon 3 of the MLH1 gene. This pathogenic mutation results from an in-frame AGA deletion of three nucleotides between nucleotide positions 213 and 215, resulting in the in frame deletion of one amino acid (glutamate) at codon 71. This mutation has been reported in numerous individuals with Lynch syndrome (Chong G et al, Hum. Mutat. 2009 Aug; 30(8):E797-812; Kansikas M et al, Hum. Mutat. 2011 Jan; 32(1):107-15; McVety S et al, J. Med. Genet. 2006 Feb; 43(2):153-6; Mangold E et al, J. Pathol. 2005 Dec; 207(4):385-95; Overbeek LI et al, Br. J. Cancer 2007 May; 96(10):1605-12; Raevaara TE et al, Gastroenterology 2005 Aug; 129(2):537-49). cDNA sequencing indicated that this alteration causes exon 3 skipping during mRNA splicing, suggesting the presence of an exon splicing enhancer (ESE) at the 5' end of exon 3, and inclusion of exon 3 in the mRNA is ESE dependent (McVety S et al. J Med Genet. 2006 Feb;43(2):153-6). Further, multiple functional analyses of this mutation have shown significantly reduced DNA repair efficiency compared to wild type (Raevaara et al. J Med Genet. 2002 Oct;39(10):747-50; Raevaara et al. Gastroenterology. 2005 Aug;129(2):537-49; Ou et al. Hum Mutat. 2007 Nov;28(11):1047-54; Kansikas et al. Hum Mutat. 2011 Jan;32(1):107-15). Of note, this alteration is also designated as c.209_211delAAG and c.211_213delGAA in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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	RCV000698898	SCV000827588	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-06-27	criteria provided, single submitter	clinical testing	This variant, c.213_215del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Glu71del), but otherwise preserves the integrity of the reading frame. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 15923275, 18561205, 23896635). Experimental studies have shown that this variant affects MLH1 function (PMID: 12362032, 16083711). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 90067). This variant is also known as 71del and c.209_211delAAG in the literature. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12362032, 16216036, 17453009, 19459153, 23896635). It has also been observed to segregate with disease in related individuals.
GeneDx	RCV000202299	SCV001759734	pathogenic	not provided	2022-01-14	criteria provided, single submitter	clinical testing	In-frame deletion of one amino acid in a non-repeat region; Observed in several individuals with personal or family history consistent with Lynch syndrome (Overbeek 2007, Chong 2009, Shigeyasu 2014, Yang 2021); Published functional studies demonstrate a damaging effect: decreased MLH1 protein expression and interaction with PMS2 as well as defective mismatch repair activity in vitro (Raevaara 2002, Raevaara 2005); RT-PCR and mRNA-based assays have found this variant causes skipping of exon 3 due to disruption of an exonic splice enhancer (McVety 2006, Shigeyasu 2014); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.209_211delAAG or c.211_213delGAA; This variant is associated with the following publications: (PMID: 17453009, 19459153, 27829276, 23896635, 21120944, 18561205, 17594722, 16216036, 25504677, 24362816, 22753075, 34178123, 12362032, 16083711, 15923275)
Institute of Human Genetics, University Hospital Muenster	RCV002287362	SCV002578078	pathogenic	Neoplasm of the large intestine	2021-12-12	criteria provided, single submitter	clinical testing	ACMG categories: PS3,PM1,PM2,PM4,PP4,PP5
Baylor Genetics	RCV000018633	SCV004190642	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-08-20	criteria provided, single submitter	clinical testing
OMIM	RCV000018633	SCV000038916	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2006-02-01	no assertion criteria provided	literature only
Mayo Clinic Laboratories, Mayo Clinic	RCV000202299	SCV000257086	pathogenic	not provided		no assertion criteria provided	research