3-37012098-C-T

Variant names:

• chr3-37012098-C-T
• rs63751615
• ENST00000458205:c.-48C>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_001167618.3(MLH1):​c.-48C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MLH1 NM_001167618.3 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.9979
• Clinical Significance: Pathogenic reviewed by expert panel P:24 U:1
• Conservation: PhyloP100: 1.21

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 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 3-37012098-C-T is Pathogenic according to our data. Variant chr3-37012098-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17087.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37012098-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.676C>T	p.Arg226*	stop_gained, splice_region_variant	Exon 8 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.676C>T	p.Arg226*	stop_gained, splice_region_variant	Exon 8 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250982 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135634

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452898 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 723392

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: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:24 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:7 Uncertain:1

Aug 22, 2019

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 27601186, 25980754, 28514183, 10874307, 21056691, 21868491, 21247423, 20924129, 20045164, 19690142, 18307539, 15655560, 9927033, 8872463, 23047549, 25525159, 17889038, 22949379, 15849733, 12624141, 21879275, 22776989, 9472100, 24344984, 24456667, 28445943, 26681312, 28449805, 28944238, 11343035, 28502729, 29478780, 28874130, 30521064, 30720243, 30262796, 29505604, 30998989, 29625052, 30217226, 32719484) -

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Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 11, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

MLH1: PVS1, PP1:Strong, PM2, PS4:Moderate -

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 12, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes the premature termination of MLH1 protein synthesis. In the published literature, this variant has been reported in individuals and families with Lynch syndrome (PMIDs: 32635641 (2020), 28944238 (2017), 28874130 (2017), 21247423 (2011), 23047549 (2012)), and constitutional mismatch repair deficiency (CMMRD) syndrome (PMID: 17889038 (2008)). The frequency of this variant in the general population, 0.000004 (1/250982 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect MLH1 mRNA splicing . Based on the available information, this variant is classified as pathogenic. -

Colorectal cancer, hereditary nonpolyposis, type 2 Pathogenic:6

Jul 19, 2017

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 27, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 16, 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 termination codon and is predicted to result in premature protein truncation. -

Feb 02, 2022

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2021

Genetics and Molecular Pathology, SA Pathology

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 -

Aug 14, 2018

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.676C>T (p.Arg226X) 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. Though the variant is located close to a canonical splice site, 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.1e-06 in 245718 control chromosomes (gnomAD). The variant, c.676C>T, has been reported in the literature as a pathogenic variant in multiple individuals affected with Lynch Syndrome (e.g. Moslein 1996, Lagerstedt-Robinson 2016, Rossi 2017, Sunga 2017. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 02, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a C to T nucleotide change in exon 8 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in multiple individuals and families affected with Lynch syndrome-associated cancer, many of whom met the Amsterdam II criteria (PMID: 9927033, 15655560, 15849733, 18307539, 19690142, 20045164, 20924129, 21247423, 24344984, 24362816, 27601186, 28514183, 28874130). This variant has also been reported in homozygous carriers affected with constitutional mismatch repair deficiency syndrome (PMID: 17889038), and has been shown to segregate with disease in families (PMID: 15655560, 21247423, 24362816). This variant has also been identified in an individual affected with ovarian cancer (PMID: 23047549). This variant has been identified in 1/250982 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Sep 05, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R226* pathogenic mutation (also known as c.676C>T), located in coding exon 8 of the MLH1 gene, results from a C to T substitution at nucleotide position 676. This changes the amino acid from an arginine to a stop codon within coding exon 8. This mutation has been detected in multiple families meeting Amsterdam Criteria for a clinical diagnosis of Hereditary Non-Polyposis Colorectal Cancer (HNPCC)/Lynch syndrome), several with tumors demonstrating microsatellite instability and loss of MLH1 protein on immunohistochemistry (Moslein G et al. Hum Mol Genet, 1996 Sep;5:1245-52; Marcos I et al. J Pediatr, 2006 Jun;148:837-9; Mueller J et al. Cancer Res, 2009 Sep;69:7053-61; Coolbaugh-Murphy MI et al. Hum Mutat, 2010 Mar;31:317-24; Chang SC et al. Surgery, 2010 May;147:720-8; Jasperson KW et al. Fam Cancer, 2010 Jun;9:99-107; Giráldez MD et al. Clin Cancer Res, 2010 Nov;16:5402-13; Limburg PJ et al. Clin Gastroenterol Hepatol, 2011 Jun;9:497-502; Castillejo A et al. BMC Med. Genet., 2011;12:12; Pal T et al. Br J Cancer, 2012 Nov;107:1783-90; Pérez-Carbonell L et al. Gut, 2012 Jun;61:865-72; Hinrichsen I et al. Mol Cancer, 2014 Jan;13:11; Dominguez-Valentin M et al. Front Oncol, 2016 Aug;6:189; Lagerstedt-Robinson K et al. Oncol Rep, 2016 Nov;36:2823-2835; Zhang J et al. Oncotarget, 2017 Apr;8:24533-24547; Espenschied CR et al. J Clin Oncol, 2017 Aug;35:2568-2575; Sunga AY et al. Cancer Genet, 2017 04;212-213:1-7; Rossi BM et al. BMC Cancer, 2017 Sep;17:623; DeRycke MS et al. Mol Genet Genomic Med, 2017 Sep;5:553-569; Gong R et al. Cancer Manag Res, 2019 Apr;11:3721-3739; Jiang W et al. Int J Cancer, 2019 05;144:2161-2168; Dámaso E et al. Cancers (Basel), 2020 Jul;12:). This mutation has been reported as homozygous in individuals with features of constitutional mismatch repair deficiency (CMMRD) syndrome (Ricciardone MD et al. Cancer Res, 1999 Jan;59:290-3; Apessos A et al. Br J Cancer, 2005 Jan;92:396-404). This mutation has also been reported in 1/327 Mexican patients with a personal and/or family history suspicious for hereditary breast and ovarian cancer syndrome (Quezada Urban R et al. Cancers (Basel), 2018 Sep;10:). 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. -

Apr 11, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a C to T nucleotide change in exon 8 of the MLH1 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in multiple individuals and families affected with Lynch syndrome-associated cancer, many of whom met the Amsterdam II criteria (PMID: 9927033, 15655560, 15849733, 18307539, 19690142, 20045164, 20924129, 21247423, 24344984, 24362816, 27601186, 28514183, 28874130). This variant has also been reported in homozygous carriers affected with constitutional mismatch repair deficiency syndrome (PMID: 17889038), and has been shown to segregate with disease in families (PMID: 15655560, 21247423, 24362816). This variant has also been identified in an individual affected with ovarian cancer (PMID: 23047549). This variant has been identified in 1/250982 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of MLH1 function is a known mechanism of disease. Based on the available evidence, this variant is classified as Pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Sep 15, 2021

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lynch syndrome 1 Pathogenic:1

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Ding PR Lab, Sun Yat-sen University Cancer Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lynch-like syndrome Pathogenic:1

Jul 01, 2019

Constitutional Genetics Lab, Leon Berard Cancer Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Muir-Torré syndrome Pathogenic:1

Jun 21, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PVS1 very strong, PS4 strong, PM2 moderated -

Hereditary nonpolyposis colorectal neoplasms Pathogenic:1

Jan 26, 2025

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.Arg226*) 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 present in population databases (rs63751615, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer and Lynch syndrome (PMID: 8872463, 10874307, 15655560, 15849733, 17889038, 21247423, 23047549, 24344984). It has also been observed to segregate with disease in related individuals. Invitae Evidence Modeling of clinical and family history, age, sex, and reported ancestry of multiple individuals with this MLH1 variant has been performed. This variant is expected to be pathogenic with a positive predictive value of at least 99%. This is a validated machine learning model that incorporates the clinical features of 1,370,736 individuals referred to our laboratory for MLH1 testing. ClinVar contains an entry for this variant (Variation ID: 17087). For these reasons, this variant has been classified as Pathogenic. -

Mismatch repair cancer syndrome 1 Pathogenic:1

May 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	41
DANN	Uncertain	1.0
Eigen	Pathogenic	0.78
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
Vest4		0.89
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.090		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: rs63751615; hg19: chr3-37053589; COSMIC: COSV51614124; COSMIC: COSV51614124;