rs63750486

chr3-37047618-ATTG-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM4_Supporting PP3 PP5_Very_Strong

The NM_000249.4(MLH1):c.1835_1837del(p.Val612del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MLH1 NM_000249.4 inframe_deletion
• Clinical Significance: Likely pathogenic reviewed by expert panel P:6 U:1
• Conservation: PhyloP100: 7.88

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 16 uncertain in NM_000249.4
• PM4: Nonframeshift variant in NON repetitive region in NM_000249.4. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 3-37047618-ATTG-A is Pathogenic according to our data. Variant chr3-37047618-ATTG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 89900.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37047618-ATTG-A is described in Lovd as [Likely_pathogenic]. Variant chr3-37047618-ATTG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.1835_1837del	p.Val612del	inframe_deletion	16/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.1835_1837del	p.Val612del	inframe_deletion	16/19	1	NM_000249.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Nov 20, 2023

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]. -

Hereditary nonpolyposis colon cancer Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 08, 2019

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. -

Lynch syndrome Pathogenic:1

Likely pathogenic, reviewed by expert panel

curation

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Jun 21, 2019

Multifactorial likelihood analysis posterior probability 0.95-0.99 -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Nov 09, 2022

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. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 16, 2023

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. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 29, 2023

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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 23, 2020

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Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs63750486; hg19: chr3-37089109;