Submissions for variant NM_000249.4(MLH1):c.2218dup (p.Ile740fs)

dbSNP: rs587778989

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075577	SCV000106574	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Frameshift interrupting C-terminus interaction domain
GeneDx	RCV000478135	SCV000567207	pathogenic	not provided	2021-04-16	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in an individual undergoing whole exome sequencing (LaDuca 2017); This variant is associated with the following publications: (PMID: 28152038)
Invitae	RCV000817894	SCV000958479	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ile740Asnfs*6) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 17 amino acid(s) of the MLH1 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 90091). 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.
Ambry Genetics	RCV002426632	SCV002728801	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-30	criteria provided, single submitter	clinical testing	The c.2218dupA pathogenic mutation, located in coding exon 19 of the MLH1 gene, results from a duplication of A at nucleotide position 2218, causing a translational frameshift with a predicted alternate stop codon (p.I740Nfs*6). This alteration occurs at the 3' terminus of MLH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 17 amnio acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). Based on internal structural assessment, this alteration disrupts the structure of the C-terminal domain at the interface with PMS2 and the heterodimeric di-zinc endonuclease site (Gueneau E et al. Nat Struct Mol Biol. 2013 Apr;20:461-8; Ambry internal data). This alteration has been identified in several individuals with MLH1 and/or PMS2 deficient colon cancers and/or families meeting Amsterdam I/II criteria (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.
Myriad Genetics, Inc.	RCV003455997	SCV004186452	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 premature protein truncation.