ClinVar Miner

Submissions for variant NM_001167617.2(MLH1):c.1958_1959dup (p.Val654fs) (rs267607901)

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Total submissions: 5
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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 2019-09-26 criteria provided, single submitter clinical testing This sequence change inserts 2 nucleotides in exon 19 of the MLH1 mRNA (c.2252_2253dupAA), causing a frameshift at codon 752 (p.Val752Lysfs*32). This is expected to replace the last 5 amino acids of the MLH1 protein with 31 amino acids, creating a new downstream translational stop signal that extends the length of the protein by 26 amino acids. While this is not anticipated to result in nonsense mediated decay, it is expected to result in a disrupted MLH1 protein. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Lynch syndrome (PMID: 18931482, 15926618, 11151427, 24344984, 15849733, 23640085). This variant is referred to as Ins AA at 2254 or c.2253_2254insAA in the literature. ClinVar contains an entry for this variant (Variation ID: 90102). While no functional studies have been performed to test the effect of this particular variant on MLH1 protein function or stability, it affects the highly conserved C-terminal domain (CTD) responsible for MLH1 constitutive dimerization with PMS2 (PMID: 12799449, 16338176, 20533529). Different frameshift variants including c.2269dup, located downstream of this variant, have been determined to be pathogenic (PMID: 8128251, 9697702, 12810663, 14985405, Invitae). This suggests that disruption of this region of the MLH1 protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001014941 SCV001175717 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-23 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color RCV001014941 SCV001347653 likely pathogenic Hereditary cancer-predisposing syndrome 2019-06-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193808 SCV001362939 pathogenic Hereditary nonpolyposis colon cancer 2019-03-07 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. The variant was absent in 277026 control chromosomes (gnomAD). c.2252_2253dupAA has been reported in the literature in individuals affected with hereditary non-polyposis colorectal cancer (Dominguez-Valentin_2013, Sheng_2008, Mangold_2005, Wolf_2005). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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