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

dbSNP: rs267607901

Total submissions: 8

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
Labcorp Genetics (formerly Invitae), Labcorp	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	2023-11-17	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 has been identified in HNPCC patients who fulfilled Bethesda and/or Amsterdam II guidelines with tumor analysis revealing MSI-H and loss of MLH1 and/or PMS2 by IHC (Pistorius SR et al. Int J Colorectal Dis. 2000 Nov;15(5-6):255-63; 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; Ambry internal data). 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). 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
Mendelics	RCV004698822	SCV005200750	likely pathogenic	Hereditary cancer	2024-08-12	criteria provided, single submitter	clinical testing
GeneDx	RCV004700378	SCV005201983	likely pathogenic	not provided	2023-08-11	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein extension, as the last 5 amino acids are replaced with 31 different amino acids, and other loss-of-function variants have been reported downstream; Not observed at significant frequency in large population cohorts (gnomAD); Also known as c.2253_2254insAA; Observed in individuals with personal and/or family history of Lynch syndrome-related cancers (Pistorius et al., 2000; Mangold et al., 2005; Wolf et al., 2005; Sheng et al., 2008; Dominguez-Valentin et al., 2013; Sui et al., 2019); This variant is associated with the following publications: (PMID: 11151427, 16338176, 24204293, 12799449, 20533529, 22753075, 28874130, 18931482, 15926618, 30614234, 31830689, 23640085, 24344984, 15849733)