3-36993599-C-T

Position:

chr3-36993599-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PP3_StrongBP6

The NM_000249.4(MLH1):c.52C>T(p.Arg18Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000688 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R18G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:15B:2O:1

Conservation

PhyloP100: 5.72

Variant links:

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]

MLH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 17 uncertain in NM_000249.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.949

BP6

Variant 3-36993599-C-T is Benign according to our data. Variant chr3-36993599-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134656.We mark this variant Likely_benign, oryginal submissions are: {not_provided=1, Likely_benign=2, Uncertain_significance=12}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.52C>T	p.Arg18Cys	missense_variant	1/19	ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.52C>T	p.Arg18Cys	missense_variant	1/19	1	NM_000249.4	P1	P40692-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251420

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135916

show subpopulations

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:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000725

AC:

106

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000688

AC XY:

AN XY:

727244

show subpopulations

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:

0.0000944

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152204

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000605

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:15Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Uncertain significance, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 05, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals suspected of having Lynch syndrome, including at least one individual whose tumor showed microsatellite instability (PMID: 21404117, 14635101, 25559809, 25980754); This variant is associated with the following publications: (PMID: 24728327, 14635101, 22949387, 21404117, 25980754, 25559809, 26296696, 32008151, 29625052, 26580448, 36451132, 32601921, 33471991, 35980532, 22753075) -
Uncertain significance, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 11, 2022	The frequency of this variant in the general population, 0.00007 (8/113708 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with colorectal cancer (PMID: 14635101 (2003), 25559809 (2015)), a Lynch syndrome associated cancer and/or polyps (PMID: 25980754 (2015), 21404117 (2011)), pediatric cancer (PMID: 26580448 (2015)), uveal melanoma (PMID: 29625052 (2018)), and breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MLH1)). It has also been reported in unaffected individuals (PMID: 24728327 (2014), PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MLH1)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	MLH1: PP3 -

not specified

Uncertain:3Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 10, 2020	Variant summary: MLH1 c.52C>T (p.Arg18Cys) results in a non-conservative amino acid change located in the N-terminal domain (IPR002099) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251420 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.52C>T has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer/Lynch Syndrome/Pediatric cancer cohort (example, Taylor_2003, Hardt_2011, Yurgelun_2015, Chubb_2015, Zhang_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=6, likely benign, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 14, 2020	DNA sequence analysis of the MLH1 gene demonstrated a sequence change, c.52C>T, in exon 1 that results in an amino acid change, p.Arg18Cys. This sequence change has been reported in a patient with early onset proximal colorectal cancer with microsatellite instability and a family history of CRC in a sibling (PMID: 25559809). It has also been reported in few other patients with colorectal cancer but no additional patient specific clinical information was provided (PMIDs: 25980754, 21404117, and 14635101). This sequence change has been described in the gnomAD database with a low population frequency of 0.0032% (dbSNP rs367654552). The p.Arg18Cys change affects a highly conserved amino acid residue located in a domain of the MLH1 protein that is known to be functional. The p.Arg18Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg18Cys change remains unknown at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	Feb 10, 2016	- -

Colorectal cancer, hereditary nonpolyposis, type 2

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 06, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 14, 2023	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Sep 09, 2016	- -

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 09, 2023	This missense variant replaces arginine with cysteine at codon 18 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 14635101, 21404117, 25559809, 25980754) or breast cancer (PMID: 32601921), and has also been in a healthy control (PMID: 24728327). This variant has been identified in 8/251420 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 04, 2019	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 16, 2021	- -

Lynch syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 13, 2023

This missense variant replaces arginine with cysteine at codon 18 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 14635101, 21404117, 25559809, 25980754) or breast cancer (PMID: 32601921), and has also been in a healthy control (PMID: 24728327). This variant has been identified in 8/251420 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

MLH1-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2023

The MLH1 c.52C>T variant is predicted to result in the amino acid substitution p.Arg18Cys. This variant has been reported in at least five individuals with either suspected Lynch syndrome or a personal and family history of colorectal cancer (Taylor et al. 2003. PubMed ID: 14635101; Hardt et al. 2011. PubMed ID: 21404117; Chubb et al. 2015. PubMed ID: 25559809; Yurgelun et al. 2015. PubMed ID: 25980754). It has also been reported in two individuals with acute lymphoblastic leukemia (Zhang et al. 2015. PubMed ID: 26580448) and one individual with uveal melanoma (Huang et al. 2018. PubMed ID: 29625052). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is classified as a variant of uncertain significance by the vast majority of sources in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/134656/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary nonpolyposis colorectal neoplasms

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 18 of the MLH1 protein (p.Arg18Cys). This variant is present in population databases (rs367654552, gnomAD 0.006%). This missense change has been observed in individual(s) with melanoma, acute lymphocytic leukemia and/or clinical features of Lynch syndrome (PMID: 14635101, 21404117, 22144684, 25980754, 26580448, 29625052). ClinVar contains an entry for this variant (Variation ID: 134656). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.61

MetaRNN

Pathogenic

0.95

MetaSVM

Pathogenic

0.88

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-5.7

REVEL

Pathogenic

0.83

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.91

MVP

0.97

MPC

0.46

ClinPred

1.0

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.74

gMVP

0.79

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over