Submissions for variant NM_000249.4(MLH1):c.2195_2198dup (p.His733fs)

dbSNP: rs267607903

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075574	SCV000106571	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Frameshift interrupting C-terminus interaction domain. Multifactorial likelihood analysis posterior probability >0.99
GeneDx	RCV000202055	SCV000566756	pathogenic	not provided	2021-05-05	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation, as the last 24 amino acids are replaced with 13 different amino acids, and other loss-of-function variants have been reported downstream (Landrum 2016); Published functional studies demonstrate a damaging effect: decreased PMS2 interaction (Kondo 2003); Observed in patients with Lynch-related cancers and tumor studies consistent with pathogenic variants in this gene (Risinger 1996, Kondo 2003, Kunstmann 2004, Chong 2009, Schiavi 2015, Rosty 2016, Yurgelun 2017); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 12810663, 15217520, 26895986, 19459153, 26628864, 8646682, 28135145, 32659967)
Ambry Genetics	RCV000567584	SCV000676014	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-06	criteria provided, single submitter	clinical testing	The c.2195_2198dupAACA pathogenic mutation, located in coding exon 19 of the MLH1 gene, results from a duplication of AACA at nucleotide position 2195, causing a translational frameshift with a predicted alternate stop codon (p.H733Qfs*14). This alteration occurs at the 3' terminus of theMLH1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 24 amino 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). This alteration has been reported in multiple individuals with hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome, several with tumors exhibiting loss of MLH1 on immunohistochemistry (Syngal S et al. JAMA, 1999 Jul;282:247-53; Wagner A et al. Am J Hum Genet, 2003 May;72:1088-100; Kunstmann E et al. BMC Med. Genet., 2004 Jun;5:16; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Ponti G et al. Clin Genet, 2015 Jun;87:507-16; Schiavi A et al. Curr Oncol, 2015 Oct;22:317-25; Rosty C et al. BMJ Open, 2016 Feb;6:e010293; Lee J et al. Gynecol Oncol, 2018 10;151:153-158; Lawrence J et al. Curr Oncol, 2021 01;28:509-522). This alteration is posited as a French-Canadian founder mutation (Chong G et al. Hum. Mutat., 2009 Aug;30:E797-812). 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	RCV000798201	SCV000937803	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-07-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 90088). This premature translational stop signal has been observed in individuals with Lynch syndrome (PMID: 8646682, 12658575, 15217520, 15849733, 19459153). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.His733Glnfs*14) in the MLH1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the MLH1 protein.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202055	SCV001134305	pathogenic	not provided	2019-06-19	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Myriad Genetics, Inc.	RCV003451116	SCV004186324	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202055	SCV000257090	pathogenic	not provided		no assertion criteria provided	research
GeneReviews	RCV001804818	SCV002054056	not provided	Lynch syndrome 1		no assertion provided	literature only