3-37028857-AC-ACC

Variant names:

• chr3-37028857-A-AC
• rs63750855
• NM_000249.4:c.1489dupC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000249.4(MLH1):​c.1489dupC​(p.Arg497ProfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MLH1 NM_000249.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:20 O:1
• Conservation: PhyloP100: 0.659

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-37028857-A-AC is Pathogenic according to our data. Variant chr3-37028857-A-AC is described in ClinVar as [Pathogenic]. Clinvar id is 89753.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.1489dupC	p.Arg497ProfsTer6	frameshift_variant	Exon 13 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.1489dupC	p.Arg497ProfsTer6	frameshift_variant	Exon 13 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:20 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:9

Feb 04, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MLH1: PVS1, PM2 -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 29, 2023

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This duplication of one nucleotide is denoted MLH1 c.1489dupC at the cDNA level and p.Arg497ProfsX6 (R497PfsX6) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ACCCCC[dupC]GGAG. The duplication causes a frameshift, which changes an Arginine to a Proline at codon 497, and creates a premature stop codon at position 6 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Also published as MLH1 c.1489_1490insC using alternate nomenclature, this variant has been reported in many individuals and families with Lynch syndrome (Kurzawski 2002, Behrens 2003, Mangold 2005, Wolf 2006, Bonadona 2011, Buchanan 2014, Magnani 2015). MLH1 c.1489dupC has also been reported in at least one individual with a clinical diagnosis of Muir-Torre syndrome (Mangold 2007). Additionally, this variant has been observed in the germline of at least two individuals with breast cancer; one breast tumor demonstrated loss of MLH1 protein on immunohistochemistry and the other breast tumor demonstrated loss of heterozygosity (Lotsari 2012, Pedroni 2014). Lastly, the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as pathogenic (Thompson 2014). Based on currently available evidence, we consider MLH1 c.1489dupC to be pathogenic. -

Dec 01, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:3

Mar 15, 2023

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

Sep 01, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 17, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome Pathogenic:3

Sep 05, 2013

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Coding sequence variation resulting in a stop codon -

Mar 23, 2016

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1489dup (p.Arg497Profs*6) variant of the MLH1 gene creates a frameshift resulting in a premature termination codon that is predicted to lead to absent or truncated protein product. This variant has been reported in multiple individuals (>20) affected with Lynch syndrome associated phenotypes including colorectal cancer, breast cancer, endometrial cancer, small bowel cancer, and hereditary nonpolyposis colorectal cancer (HNPCC) (PMID: 17199584, 15849733, 8872463, 27535758, 15765394, 23695190, 15926618). In addition, this variant has been found in breast ductal tumors demonstrating microsatellite instability and loss of MLH1 protein expression by immunohistochemistry (PMID: 22691310). In vitro yeast two-hybrid assay demonstrated that the predicted truncated protein failed to interact with PMS2 protein (PMID:?12810663). Loss of function variants of the MLH1 gene are known to be pathogenic (PMID: 14635101, 15942939, 16955466, 15713769, 24362816, 33468175). Truncating variants downstream of this variant are reported to be pathogenic in the literature (PMID: 8571956, 12810663, 15849733, 20459533) and by several ClinVar submitters (ClinVar ID: 89754, 89888, 89889, 439171). This variant is absent in the general population database (gnomAD) and classified as pathogenic by expert panel (ClinVar ID: 89753). Therefore, the c.1489dup (p.Arg497Profs*6) variant in the MLH1 gene is classified as pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Jun 11, 2019

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary nonpolyposis colon cancer Pathogenic:1

Mar 26, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MLH1 c.1489dupC (p.Arg497ProfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 277234 control chromosomes (gnomAD). c.1489dupC has been reported in the literature in multiple individuals affected with Lynch Syndrome (Kamiza_2015, Kurzawski_2006, Kondo_2003). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated that there was no interaction between the predicted truncated protein and PMS2 (Kondo_2003). Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jul 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg497Profs*6) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Lynch syndrome or Lynch syndrome associated cancers (PMID: 1756143, 8872463, 12810663, 15849733, 15926618, 18566915, 21598002, 22691310, 23695190, 24323032, 26053027). Invitae’s Lynch syndrome clinical variant model, which takes into account the clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant, predicts that it is pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model developed at Invitae that incorporates the clinical features of 1,370,736 individuals referred for testing at Invitae. ClinVar contains an entry for this variant (Variation ID: 89753). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

May 02, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1489dupC pathogenic mutation, located in coding exon 13 of the MLH1 gene, results from a duplication of C at nucleotide position 1489, causing a translational frameshift with a predicted alternate stop codon (p.R497Pfs*6). This mutation has been reported in multiple studies of patients with Lynch syndrome, including those meeting Amsterdam criteria and/or with tumors demonstrating microsatellite instability or loss of MLH1 protein expression by IHC (Moslein G et al. Hum. Mol. Genet., 1996 Sep;5:1245-52; Mangold E et al. Int J Cancer, 2005 Sep;116:692-702; Papp J et al. World J Gastroenterol, 2007 May;13:2727-32; Kast K et al. Arch Gynecol Obstet, 2016 11;294:1299-1303). This mutation was also present in individuals from HNPCC families with Muir-Torre features (Mangold E et al. Br J Dermatol, 2007 Jan;156:158-62), small bowel cancer (Schulmann K et al. Gastroenterology, 2005 Mar;128:590-9), breast cancer (Lotsari JE et al. Breast Cancer Res., 2012 Jun;14:R90), and a neuroendocrine pancreatic tumor (Brieger A et al. Fam Cancer, 2011 Sep;10:591-5). Of note, this mutation is also designated as c.1489_1490insC and 495insC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Endometrial carcinoma Pathogenic:1

Feb 21, 2023

CZECANCA consortium

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch syndrome 1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

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: rs63750855; hg19: chr3-37070348;