ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.2252_2253dup (p.Val752fs)

dbSNP: rs267607901
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075588 SCV000106584 uncertain significance Lynch syndrome 2019-06-21 reviewed by expert panel curation Insufficient evidence: extends protein by 26 amino acids
Invitae RCV000524283 SCV000284055 pathogenic Hereditary nonpolyposis colorectal neoplasms 2022-09-21 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.*757Leuext*33) have been determined to be pathogenic (PMID: 8128251, 9697702, 12810663, 14985405). 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: 90102). This variant is also known as Ins AA at 2254 or c.2253_2254insAA. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 11151427, 15849733, 15926618, 18931482, 23640085, 24344984). This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the MLH1 gene (p.Val752Lysfs*32). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the MLH1 protein.
Ambry Genetics RCV001014941 SCV001175717 likely pathogenic Hereditary cancer-predisposing syndrome 2021-05-24 criteria provided, single submitter clinical testing The c.2252_2253dupAA variant, located in coding exon 19 of the MLH1 gene, results from a duplication of AA at nucleotide positions 2252 and 2253, causing a translational frameshift with a predicted alternate stop codon (p.Val752Lysfs*32). This alteration occurs only five amino acids prior to the normal termination codon, and is predicted to elongate MLH1 by 26 amino acids. This variant was identified in an HNPCC patient who fulfilled Bethesda guidelines with tumor analysis revealing MSI-H and loss of MLH1 by IHC (Pistorius SR et al. Int J Colorectal Dis. 2000 Nov;15(5-6):255-63). This variant has also been reported in numerous studies of patients either diagnosed with HNPCC or were suspected to have HNPCC and either met Bethesda guidelines or Amsterdam I/II criteria (Sheng JQ et al. Cytogenet. Genome Res. 2008;122(1):22-7; Wolf B et al. Wien. Klin. Wochenschr. 2005 Apr;117(7-8):269-77; Mangold E et al. Int. J. Cancer. 2005 Sep;116(5):692-702; Fu L et al. Cell Oncol (Dordr). 2013 Jun;36:225-31; Rossi BM et al. BMC Cancer. 2017 Sep;17:623). Structural analysis shows that this alteration perturbs a known functional domain responsible for binding to PMS2 and removes a cysteine residue shown to be involved in metal binding as part of a functional domain in PMS2 (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 amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Diagnostics, LLC DBA Color Health RCV001014941 SCV001347653 likely pathogenic Hereditary cancer-predisposing syndrome 2019-06-28 criteria provided, single submitter clinical testing This variant inserts 2 nucleotides in exon 19 of the MLH1 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in multiple hereditary nonpolyposis colorectal cancer (HNPCC) families (PMID: 15849733, 15926618, 18931482). This variant has been reported to segregate with disease (InSiGHT database; http://insight-database.org/classifications/index.html?gene=MLH1&variant=c.2252_2253dup). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193808 SCV001362939 pathogenic Hereditary nonpolyposis colon cancer 2023-01-23 criteria provided, single submitter clinical testing Variant summary: MLH1 c.2252_2253dupAA (p.Val752LysfsX32) causes a frameshift which results in an extension of the protein in the carboxy terminal homology domain (Sui_2019). The variant was absent in 251302 control chromosomes. c.2252_2253dupAA has been reported in the literature in multiple individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Dominguez-Valentin_2013, Sheng_2008, Mangold_2005, Wolf_2005, Sui_2019). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four (other) submitters including an expert panel have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=3) or VUS (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003460708 SCV004193078 likely pathogenic Colorectal cancer, hereditary nonpolyposis, type 2 2021-02-25 criteria provided, single submitter clinical testing

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