ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1832TTG[1] (p.Val612del) (rs63750486)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075377 SCV000106372 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.95-0.99
Invitae RCV001201372 SCV000543647 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-13 criteria provided, single submitter clinical testing This variant, c.1835_1837del, results in the deletion of 1 amino acid(s) of the MLH1 protein (p.Val612del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15849733, 16083711, 21404117, Invitae). Based on a multifactorial likelihood algorithm using genetic, clinical, in silico and functional data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). Also, this variant has been reported to affect MLH1 protein function (PMID: 16083711). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000574309 SCV000673841 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-06 criteria provided, single submitter clinical testing The c.1835_1837delTTG variant (also known as p.V612del) is located in coding exon 16 of the MLH1 gene. This variant results from an in-frame TTG deletion at nucleotide positions 1835 to 1837, causing the removal of a valine residue at codon 612. This alteration has been reported in an individual with a family history that met Amsterdam I criteria and who was diagnosed with a MSI-H colorectal cancer that displayed loss of MLH1 expression on immunohistochemistry (Raevaara TE et al. Gastroenterology. 2005 Aug;129(2):537-49; Mangold E et al. J Pathol. 2005 Dec;207(4):385-95; Hardt K et al. Fam Cancer. 2011 Jun;10(2):273-84). Functional studies of this alteration showed decreased expression in 293T cells and aberrant nuclear localization (Raevaara TE et al. Gastroenterology. 2005 Aug;129(2):537-49). This alteration has been classified as likely pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at []). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by PROVEAN in silico analysis (Choi Y et al., PLoS ONE 2012 ;7(10):e46688). Based on internal structural analysis, this alteration is expected to result in substantial structural rearrangement in a helix of the dimerization domain where other pathogenic missense alterations are present. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193960 SCV001363156 likely pathogenic Hereditary nonpolyposis colon cancer 2019-03-08 criteria provided, single submitter clinical testing Variant summary: MLH1 c.1835_1837delTTG (p.Val612del) results in an in-frame deletion that is predicted to remove a valine from the encoded protein located in the C-terminal domain (IPR032189), which contains the region where MLH1 interacts with PMS2 (Raevaara 2005). The variant was absent in 277146 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1835_1837delTTG has been reported in the literature in individuals affected with Lynch Syndrome, with at least one family that fulfilled the Amsterdam I criteria (Mangold 2005, Raevaara 2005, Hardt 2011), where the associated tumors demonstrated the loss of MLH1 expression (IHC) and increased microsatellite stability (Mangold 2005, Hardt 2011). A functional study demonstrated that the variant resulted in protein instability with considerably decreased MLH1 (and PMS2) quantities, and the variant MLH1 protein had about 76% relative repair activity, with somewhat reduced nuclear localization (Raevaara 2005). Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant once as likely pathogenic and once as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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