Submissions for variant NM_000249.4(MLH1):c.2266_2269dup (p.Ter757LeuextTer?)

dbSNP: rs267607892

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075593	SCV000106590	pathogenic	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability >0.99
GeneDx	RCV000201988	SCV000617553	pathogenic	not provided	2020-09-10	criteria provided, single submitter	clinical testing	This duplication of 4 nucleotides in MLH1 is denoted c.2266_2269dupTGTT at the cDNA level andp.X757LextX35 at the protein level. The normal sequence, with the bases that are duplicated in brackets, isGAGG[dupTGTT]AAat where the capital letters are exonic and lowercase are intronic. The duplication causes aframeshift, which changes a stop codon to a Leucine at codon 2266 in the last exon of the gene, and results in anextension of the protein. The native termination codon is replaced by 34 incorrect amino acids. This variant, alsopublished as 2266ins4 or 756ins4bp, was found to segregate with disease in a large family that met Amsterdam IIcriteria (Lynch 1990, Papadopoulos 1994, Boyd 1999). Internal observations also show this variant segregating inindividuals with personal histories consistent with Lynch syndrome. This variant was shown to lead to a reduction in thedominant mutator effect, near absent beta-gal activity, and decreased interaction with PMS2 (Shimodaira 1998, Kondo2003). In addition, The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifiesthis variant as pathogenic (Thompson 2014). Based on currently available information, we consider this to be a pathogenic variant.
Invitae	RCV000817018	SCV000957554	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-01	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the MLH1 gene (p.*757Leuext*34). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the stop codon of the MLH1 protein and extend the protein by 34 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 2224779, 8128251, 10206076; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as 755_756ins4 and 756ins4. ClinVar contains an entry for this variant (Variation ID: 90107). 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, 12810663). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001269209	SCV001448515	pathogenic	Hereditary nonpolyposis colon cancer	2020-11-06	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.2266_2269dupTGTT (p.X757LeufsX35) causes a frameshift which results in an extension of the protein with additional 34 amino acids. The variant was absent in 251260 control chromosomes (gnomAD). c.2266_2269dupTGTT has been reported in the literature in individuals affected with colorectal cancer and Lynch syndrome and this variant was shown to segregate with disease in a family (Papadopoulos_1994, Liu_1996, Boyd_1999, ClinVar labs). These data indicate that the variant may be associated with disease. In vitro studies report this variant reduced mutation rate, beta-gal activity and results in decreasing the interaction with associated proteins. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. In addition, one expert panel, International Society for Gastrointestinal Hereditary Tumours (InSiGHT), classified this variant as pathogenic in ClinVar in 2013 (Thompson_2014). Based on the evidence outlined above, the variant was classified as pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000201988	SCV002047711	pathogenic	not provided	2021-06-08	criteria provided, single submitter	clinical testing	The MLH1 c.2266_2269dupTGTT; p.Ter757LeuextTer34 variant, is reported in the literature in multiple individuals affected with Lynch syndrome and segregates with disease in a large kindred (Boyd 1999, Lynch 1990, Papadopoulos 1994). In vitro/In vivo functional analyses demonstrate a reduction in the dominant mutator effect and a decreased interaction with PMS2 (Kondo 2003, Shimodaira 1998). This variant is reported in ClinVar (Variation ID: 90107). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by inserting four nucleotides resulting in the disruption of the stop codon and the extension of the protein with an additional 34 amino acids. Based on available information, this variant is considered to be pathogenic. References: Boyd J et al. Male breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat. 1999 Jan;53(1):87-91. PMID: 10206076. Kondo E et al. A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations. Cancer Res. 2003 Jun 15;63(12):3302-8. PMID: 12810663. Lynch HT et al. Genetic diagnosis of Lynch syndrome II in an extended colorectal cancer-prone family. Cancer. 1990 Nov 15;66(10):2233-8. PMID: 2224779. Papadopoulos N et al. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994 Mar 18;263(5153):1625-9. PMID: 8128251. Shimodaira H et al. Functional analysis of human MLH1 mutations in Saccharomyces cerevisiae. Nat Genet. 1998 Aug;19(4):384-9. PMID: 9697702.
Ambry Genetics	RCV002444529	SCV002736591	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-23	criteria provided, single submitter	clinical testing	The c.2266_2269dupTGTT pathogenic mutation (also known as p.*757Lext*34), located in coding exon 19 of the MLH1 gene, results from a duplication of TGTT at nucleotide position 2266. This alteration disrupts the stop codon of the MLH1 gene and is predicted to preserve the native sequence while resulting in the elongation of the protein by 34 amino acids. However, this alteration has been reported in Lynch syndrome families and showed moderate segregation with disease in these families (Ambry internal data; Lynch HT et al. Cancer, 1990 Nov;66:2233-8; Papadopoulos N et al. Science, 1994 Mar;263:1625-9; Liu B et al. Nat. Med., 1996 Feb;2:169-74 Boyd J et al. Breast Cancer Res. Treat., 1999 Jan;53:87-91; ). Functional studies performed in yeast demonstrated defective PMS2 interaction and a reduced dominant mutator effect for this alteration (Kondo E et al. Cancer Res., 2003 Jun;63:3302-8; Shimodaira H et al. Nat. Genet., 1998 Aug;19:384-9). Based on an internal structural assessment, this alteration is expected to detrimentally impact MLH1/PMS2 dimerization by binding to the dimerization interface (Ambry internal data). Of note, this alteration is often described as a 4-bp insertion in codons 755-756 in published literature. 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.
Baylor Genetics	RCV003460709	SCV004195051	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-17	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000201988	SCV000257092	pathogenic	not provided		no assertion criteria provided	research