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

dbSNP: rs63750486

Total submissions: 7

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	2023-07-16	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 (gnomAD no frequency). This variant has been observed in individuals with clinical features of Lynch syndrome (PMID: 15849733, 16083711, 21404117; Invitae). ClinVar contains an entry for this variant (Variation ID: 89900). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 24362816). Experimental studies have shown that this variant affects MLH1 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	2023-12-29	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. This results in the in-frame deletion of a valine 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 [www.insight-group.org/variants/classifications/]). 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. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). 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.
Genetic Services Laboratory, University of Chicago	RCV001818239	SCV002067448	uncertain significance	not specified	2020-03-23	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003451071	SCV004186066	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-11-20	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 16083711]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 37643636, 16083711, 21404117].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477466	SCV004220854	likely pathogenic	not provided	2022-11-09	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Lynch syndrome fulfilling Amsterdam 1 criteria (PMIDs: 15849733 (2005), 16083711 (2005), and 21120944 (2011)), with tumors that display loss of MLH1 expression and increased microsatellite instability (PMIDs: 15849733 (2005), 16083711 (2005), and 21404117 (2011)). Functional studies show the variant is damaging to protein function by decreasing MLH1 expression and causing improper nuclear localization (PMIDs: 16083711 (2005) and 21120944 (2011)). Additionally, multifactorial likelihood analysis predicts a high probability that this variant is pathogenic (PMID: 243362816 (2014)). Based on the available information, this variant is classified as likely pathogenic.