Submissions for variant NM_000249.4(MLH1):c.2179_2182del (p.His727fs)

dbSNP: rs267607898

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075569	SCV000106566	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
Ambry Genetics	RCV000164558	SCV000215216	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-19	criteria provided, single submitter	clinical testing	The c.2179_2182delCACA pathogenic mutation, located in coding exon 19 of the MLH1 gene, results from a deletion of 4 nucleotides at nucleotide positions 2179 to 2182, causing a translational frameshift with a predicted alternate stop codon (p.H727Ffs*55). This alteration occurs at the 3' terminus of theMLH1 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 24 amino acids. This frameshift impacts the last 30amino acids of the native protein. However, frameshifts are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This mutation has been described in a large Native American HNPCC/Lynch syndrome kindred and was shown to segregate with disease in numerous affected individuals (Lynch HT et al. Cancer. 1996 Jan;77(1):30-5). This mutation has also been identified in several individuals whose tumors demonstrated high microsatellite instability and/or loss of MLH1 and PMS2 on immunohistochemistry; some with family histories meeting Amsterdam criteria (Ambry internal data). Functional analysis determined that this alteration has reduced activity in several in vitro studies (Kondo E et al. Cancer Res. 2003 Jun;63(12):3302-8; Shimodaira H et al. Nat. Genet. 1998 Aug;19(4):384-9). Structural analysis shows that this mutation perturbs a known functional domain responsible for binding to PMS2 and removes a cysteine residue shown to be involved in metal binding (Mohd AB et al. DNA Repair (Amst.) 2006 Mar;5(3):347-61; Smith CE et al. PLoS Genet. 2013 Oct;9(10):e1003869). 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	RCV000524280	SCV000253791	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-12-14	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the MLH1 gene (p.His727Phefs*55). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 30 amino acid(s) of the MLH1 protein and extend the protein by 24 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with hereditary non-polyposis colorectal cancer or Lynch syndrome (PMID: 8128251, 8630936, 12810663). This variant is also known as 726–727 del 4bp. ClinVar contains an entry for this variant (Variation ID: 90083). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this frameshift affects MLH1 function (PMID: 9697702). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Lys751Serfs*3) have been determined to be pathogenic (PMID: 8797773, 18566915, 18931482, 24802709, 27295708). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000202306	SCV000279086	pathogenic	not provided	2021-01-29	criteria provided, single submitter	clinical testing	Frameshift variant in the C-terminus predicted to critically alter the protein, as the last 30 amino acids are replaced with 54 different amino acids; Published functional studies demonstrate a damaging effect: inability to induce dominant mutator effect and impaired interaction with PMS2 (Shimodaira 1998, Kondo 2003); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 8128251, 12810663, 8630936, 24362816, 9697702, 32719484)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202306	SCV000889399	pathogenic	not provided	2022-09-15	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the MLH1 mRNA and causes the premature termination of MLH1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in families with colorectal cancer and Lynch syndrome (PMID: 8128251 (1994), 8630936 (1996), and 12810663 (2003)). Additionally, experimental evidence suggests that this variant abolishes the interaction between MLH1 and PMS2 (PMID: 12810663 (2003)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003451113	SCV004186335	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8128251].
Baylor Genetics	RCV003451113	SCV004195091	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-09-29	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202306	SCV000257089	pathogenic	not provided		no assertion criteria provided	research