Submissions for variant NM_000249.4(MLH1):c.2070_2071insTT (p.Ile691fs)

dbSNP: rs876659681

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221270	SCV000276394	pathogenic	Hereditary cancer-predisposing syndrome	2019-04-24	criteria provided, single submitter	clinical testing	The c.2070_2071insTT pathogenic mutation, located in coding exon 18 of the MLH1 gene, results from an insertion of two nucleotides at position 2070, causing a translational frameshift with a predicted alternate stop codon (p.I691Lfs*93). This frameshift, which occurs at the 3' terminus of MLH1, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 66 amino acids of the protein in addition to elongating the protein by 26 amino acids. Structural analysis shows that this alteration perturbs a known functional domain responsible for binding to and stabilizing PMS2 and removes a cysteine residue shown to be involved in metal binding as part of a functional domain in PMS2 (Ambry internal data; Mohd AB et al. DNA Repair (Amst.) 2006 Mar;5(3):347-61; Smith CE et al. PLoS Genet. 2013 Oct;9(10):e1003869). A similar alteration, MLH1 c.2269-2270insT located in the last codon of the gene is predicted to displace the termination codon downstream and extends the protein by 33 amino acids. Based on haplotype analysis, this alteration is considered an Italian founder mutation. The vast majority of tumors from mutation carriers demonstrated microsatellite instability and loss of MLH1 on immunohistochemical staining. There was also complete segregation with Lynch-related cancers in all informative families, nearly all of whom fulfilled Amsterdam criteria (Caluseriu O et al. J. Med. Genet. 2004 Mar;41(3):e34; Ambry internal data). The c.2070_2071insTT mutation has been detected in multiple individuals whose families meet Amsterdam criteria, and whose tumors show microsatellite instability and/or absence of MLH1 and PMS2 on immunohistochemical staining (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000508512	SCV000601386	likely pathogenic	not provided	2016-10-06	criteria provided, single submitter	clinical testing
Invitae	RCV000543770	SCV000625120	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-27	criteria provided, single submitter	clinical testing	This variant disrupts a region of the MLH1 protein in which other variant(s) (p.Tyr750*, p.Lys732*, p.Ser726*) have been determined to be pathogenic (PMID: 10422993, 10923051, 25197397; Invitae). 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. ClinVar contains an entry for this variant (Variation ID: 232298). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the MLH1 gene (p.Ile691Leufs*93). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acid(s) of the MLH1 protein and extend the protein by 26 additional amino acid residues.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000659877	SCV000781764	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2016-11-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000659877	SCV004193065	pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2021-10-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000221270	SCV004359269	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This variant inserts 2 nucleotides in exon 18 of the MLH1 gene, creating a frameshift predicted to result in an alternate stop codon. This variant is expected to escape nonsense mediated decay, and impacts the last 66 amino acids of the MLH1 protein and extends the protein by 26 amino acids. Although functional studies have not been reported for the variant, it is expected to disrupt the PMS2/MLH3/PMS1 interacting domain (PMID: 12799449, 16338176, 20533529). This variant has been reported in individuals affected with Lynch syndrome (ClinVar SCV000276394.6) and in an individual affected with colorectal cancer with family history and clinical features suspect of Lynch syndrome (PMID: 28135145). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
All of Us Research Program, National Institutes of Health	RCV003997961	SCV004843267	pathogenic	Lynch syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This variant inserts 2 nucleotides in exon 18 of the MLH1 gene, creating a frameshift predicted to result in an alternate stop codon. This variant is expected to escape nonsense mediated decay, and impacts the last 66 amino acids of the MLH1 protein and extends the protein by 26 amino acids. Although functional studies have not been reported for the variant, it is expected to disrupt the PMS2/MLH3/PMS1 interacting domain (PMID: 12799449, 16338176, 20533529). This variant has been reported in individuals affected with Lynch syndrome (ClinVar SCV000276394.6) and in an individual affected with colorectal cancer with family history and clinical features suspect of Lynch syndrome (PMID: 28135145). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.