Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM4_SupportingPP3PP5_Very_Strong
The ENST00000231790.8(MLH1):c.213_215del(p.Glu71del) variant causes a inframe deletion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. K70K) has been classified as Likely benign.
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in ENST00000231790.8
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in ENST00000231790.8. Strenght limited to Supporting due to length of the change: 1aa.
PP3
Multiple lines of computational evidence support a deleterious effect 2: max_spliceai, phyloP100way_vertebrate [when was below the threshold]
PP5
Variant 3-37000955-AAAG-A is Pathogenic according to our data. Variant chr3-37000955-AAAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 90067.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37000955-AAAG-A is described in Lovd as [Pathogenic]. Variant chr3-37000955-AAAG-A is described in Lovd as [Likely_pathogenic].
Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
Baylor Genetics
Aug 20, 2023
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Pathogenic, no assertion criteria provided
literature only
OMIM
Feb 01, 2006
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not provided Pathogenic:2
Pathogenic, criteria provided, single submitter
clinical testing
GeneDx
Jan 14, 2022
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) -
Pathogenic, no assertion criteria provided
research
Mayo Clinic Laboratories, Mayo Clinic
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See cases Pathogenic:1
Pathogenic, criteria provided, single submitter
clinical testing
Institute of Human Genetics, University Hospital Muenster
Dec 12, 2021
ACMG categories: PS3,PM1,PM2,PM4,PP4,PP5 -
Lynch syndrome Pathogenic:1
Pathogenic, reviewed by expert panel
research
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Sep 05, 2013
Variant allele causes in-frame splicing aberration interrupting ATPase domain: full inactivation of variant allele -
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. -
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. -