chr3-37050534-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

The NM_000249.4(MLH1):​c.2152C>T​(p.His718Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00404 in 1,614,142 control chromosomes in the GnomAD database, including 222 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H718P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.022 ( 115 hom., cov: 33)
Exomes 𝑓: 0.0022 ( 107 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

7
7
4

Clinical Significance

Benign reviewed by expert panel U:1B:30O:1

Conservation

PhyloP100: 7.72
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5
Other missense variant is known to change same aminoacid residue: Variant chr3-37050535-A-C is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.004170716).
BP6
Variant 3-37050534-C-T is Benign according to our data. Variant chr3-37050534-C-T is described in ClinVar as [Benign]. Clinvar id is 36547.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37050534-C-T is described in Lovd as [Benign]. Variant chr3-37050534-C-T is described in Lovd as [Pathogenic].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0736 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MLH1NM_000249.4 linkc.2152C>T p.His718Tyr missense_variant Exon 19 of 19 ENST00000231790.8 NP_000240.1 P40692-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MLH1ENST00000231790.8 linkc.2152C>T p.His718Tyr missense_variant Exon 19 of 19 1 NM_000249.4 ENSP00000231790.3 P40692-1

Frequencies

GnomAD3 genomes
AF:
0.0217
AC:
3306
AN:
152196
Hom.:
113
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0758
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00792
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000176
Gnomad OTH
AF:
0.0138
GnomAD3 exomes
AF:
0.00563
AC:
1415
AN:
251118
Hom.:
59
AF XY:
0.00410
AC XY:
557
AN XY:
135700
show subpopulations
Gnomad AFR exome
AF:
0.0788
Gnomad AMR exome
AF:
0.00275
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000980
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000203
Gnomad OTH exome
AF:
0.00212
GnomAD4 exome
AF:
0.00219
AC:
3208
AN:
1461828
Hom.:
107
Cov.:
31
AF XY:
0.00191
AC XY:
1391
AN XY:
727216
show subpopulations
Gnomad4 AFR exome
AF:
0.0783
Gnomad4 AMR exome
AF:
0.00342
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000174
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000123
Gnomad4 OTH exome
AF:
0.00439
GnomAD4 genome
AF:
0.0217
AC:
3310
AN:
152314
Hom.:
115
Cov.:
33
AF XY:
0.0207
AC XY:
1543
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0758
Gnomad4 AMR
AF:
0.00784
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000176
Gnomad4 OTH
AF:
0.0137
Alfa
AF:
0.00356
Hom.:
28
Bravo
AF:
0.0247
ESP6500AA
AF:
0.0704
AC:
310
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00698
AC:
848
Asia WGS
AF:
0.00577
AC:
20
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.000296

ClinVar

Significance: Benign
Submissions summary: Uncertain:1Benign:30Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

not specified Benign:9Other:1
Dec 14, 2011
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The His718Tyr variant (rs2020873) in MLH1 is present in various populations at f requencies ranging from ~1% to ~16% and is more common individuals with African ancestry. In addition, this variant was reported in patient and control chromoso mes with equal frequncy (Barnetson 2008, Moussa 2011, Weber 1999). Finally, func tional studies have shown the His718Tyr has no discernbile impact on the functio n of the MMR complex (Martinez 2010, Kondo 2003). Therefore this variant is beni gn and not expected to have clinical significance. -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 18, 2013
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Mayo Clinic Laboratories, Mayo Clinic
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 10, 2013
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:5
Jan 01, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 30, 2020
Sema4, Sema4
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Oct 26, 2017
True Health Diagnostics
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Nov 18, 2014
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as 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. -

Dec 20, 2022
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1Benign:3
Jan 23, 2018
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Nov 11, 2016
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome Benign:4
Oct 26, 2011
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 05, 2013
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
Significance: Benign
Review Status: reviewed by expert panel
Collection Method: research

MAF >1% -

Feb 05, 2015
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Oct 01, 2024
All of Us Research Program, National Institutes of Health
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:4
Jul 13, 2012
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: research

- -

Mar 25, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

MLH1: PM5, BS1, BS2 -

Carcinoma of colon Benign:1
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

The MLH1 p.His718Tyr variant was identified in 6 of 2626 proband chromosomes (frequency: 0.002) from individuals with sporadic colorectal cancer or suspected HNPCC, none of whom met complete requirements of the Amsterdam or Bethesda criteria (Kim 2004, Kondo 2003, Takahashi 2007, Moussa 2011, Schafmayer 2007). This variant was also identified in 17 of 2254 control chromosomes from the above studies (frequency: 0.008), in the 1000 Genomes Project with a frequency of 0.028, and in the Exome Variant Server ESP Project with a frequency of 0.07 amongst African American alleles, suggesting that this variant may represent a benign polymorphism in certain populations. The variant was also reported in dbSNP (rs2020873) and LOVD. In vitro MMR assays and yeast hybrid-two assays examining the ability of the variant to repair a heteroduplex DNA with mismatch bases found that its activity was similar to that of wildtype (Kondo 2003, Takahashi 2007), suggesting that this is a nonpathogenic alteration. The p.His718 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.His718Tyr variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, we cannot determine the clinical significance of this variant with certainty at this time, although we would lean towards a more benign role for this variant. In summary, this variant is classified as predicted benign. -

Breast and/or ovarian cancer Benign:1
Oct 29, 2021
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Lynch syndrome 1 Benign:1
Jul 24, 2014
Pathway Genomics
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Muir-Torré syndrome Benign:1
Feb 01, 2025
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.22
BayesDel_addAF
Uncertain
0.019
T
BayesDel_noAF
Pathogenic
0.31
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D;.;.;.;.;.
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.88
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.93
D;D;.;.;.;D
MetaRNN
Benign
0.0042
T;T;T;T;T;T
MetaSVM
Benign
-0.54
T
MutationAssessor
Pathogenic
3.3
M;.;.;.;.;.
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-5.3
D;.;D;D;D;D
REVEL
Pathogenic
0.90
Sift
Uncertain
0.0010
D;.;D;D;D;D
Sift4G
Uncertain
0.0020
D;D;D;D;D;D
Polyphen
0.97
D;.;.;.;.;.
Vest4
0.78
MVP
0.89
MPC
0.23
ClinPred
0.027
T
GERP RS
5.4
Varity_R
0.89
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs2020873; hg19: chr3-37092025; COSMIC: COSV51620023; COSMIC: COSV51620023; API