chr3-37050534-C-T

Variant names:

• chr3-37050534-C-T
• rs2020873
• NM_000249.4:c.2152C>T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign reviewed by expert panel U:1 B:30 O:1
• Conservation: PhyloP100: 7.72

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 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
MLH1	NM_000249.4	c.2152C>T	p.His718Tyr	missense_variant	Exon 19 of 19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.2152C>T	p.His718Tyr	missense_variant	Exon 19 of 19	1	NM_000249.4	ENSP00000231790.3

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3306 AN: 152196 Hom.: 113 Cov.: 33

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

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

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

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:1 Benign:30 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9 Other:1

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 14, 2011	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. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Mar 04, 2025	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 10, 2013	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 01, 2022	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 30, 2020	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	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. -
Benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Dec 20, 2022	- -

Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 23, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Nov 11, 2016	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Lynch syndrome Benign:4

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 26, 2011	- -
Benign, reviewed by expert panel	research	International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	Sep 05, 2013	MAF >1% -
Likely benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 05, 2015	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Oct 01, 2024	- -

not provided Benign:4

Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 25, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	MLH1: PM5, BS1, BS2 -

Carcinoma of colon Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

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

Benign, criteria provided, single submitter

clinical testing

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

Oct 29, 2021

- -

Lynch syndrome 1 Benign:1

Benign, no assertion criteria provided

clinical testing

Pathway Genomics

Jul 24, 2014

- -

Muir-Torré syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Feb 01, 2025

- -

Hereditary nonpolyposis colorectal neoplasms Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2025

- -

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

Other links and lift over

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