3-37012077-A-G

Variant names:

• chr3-37012077-A-G
• rs1799977
• NM_000249.4:c.655A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000249.4(MLH1):​c.655A>G​(p.Ile219Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,610,830 control chromosomes in the GnomAD database, including 71,241 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I219L) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.23 (4935 hom., cov: 32)
  • Exomes 𝑓: 0.29 (66306 hom.)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Benign reviewed by expert panel B:31 O:1
• Conservation: PhyloP100: 2.05
• Publications: 254 publications found

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 Gene-Disease associations (from GenCC):

• Lynch syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Lynch syndrome 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
• Muir-Torre syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, G2P, Orphanet
• mismatch repair cancer syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• Lynch syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• ovarian cancer

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• malignant pancreatic neoplasm

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• breast cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 36 uncertain in NM_000249.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0014769137).
• BP6: Variant 3-37012077-A-G is Benign according to our data. Variant chr3-37012077-A-G is described in ClinVar as Benign. ClinVar VariationId is 36557.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.321 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000249.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	NM_000249.4	MANE Select	c.655A>G	p.Ile219Val	missense	Exon 8 of 19	NP_000240.1
	MLH1	NM_001354628.2		c.655A>G	p.Ile219Val	missense	Exon 8 of 18	NP_001341557.1
	MLH1	NM_001354629.2		c.556A>G	p.Ile186Val	missense	Exon 7 of 18	NP_001341558.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000231790.8	TSL:1 MANE Select	c.655A>G	p.Ile219Val	missense	Exon 8 of 19	ENSP00000231790.3
	MLH1	ENST00000456676.7	TSL:1	c.655A>G	p.Ile219Val	missense	Exon 8 of 17	ENSP00000416687.3
	MLH1	ENST00000413740.2	TSL:1	c.655A>G	p.Ile219Val	missense	Exon 8 of 15	ENSP00000416476.2

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34464 AN: 152022 Hom.: 4934 Cov.: 32

Gnomad AFR AF: 0.0798

Gnomad AMI AF: 0.426

Gnomad AMR AF: 0.222

Gnomad ASJ AF: 0.278

Gnomad EAS AF: 0.0277

Gnomad SAS AF: 0.126

Gnomad FIN AF: 0.289

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.230

GnomAD2 exomes AF: 0.233 AC: 58439 AN: 251064 AF XY: 0.237

Gnomad AFR exome AF: 0.0770

Gnomad AMR exome AF: 0.165

Gnomad ASJ exome AF: 0.288

Gnomad EAS exome AF: 0.0203

Gnomad FIN exome AF: 0.290

Gnomad NFE exome AF: 0.319

Gnomad OTH exome AF: 0.260

GnomAD4 exome AF: 0.290 AC: 423077 AN: 1458690 Hom.: 66306 Cov.: 32 AF XY: 0.287 AC XY: 208258 AN XY: 725862

African (AFR) AF: 0.0757 AC: 2531 AN: 33454

American (AMR) AF: 0.171 AC: 7669 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.292 AC: 7613 AN: 26104

East Asian (EAS) AF: 0.0374 AC: 1485 AN: 39690

South Asian (SAS) AF: 0.136 AC: 11689 AN: 86226

European-Finnish (FIN) AF: 0.295 AC: 15773 AN: 53408

Middle Eastern (MID) AF: 0.260 AC: 1499 AN: 5758

European-Non Finnish (NFE) AF: 0.324 AC: 359002 AN: 1109010

Other (OTH) AF: 0.262 AC: 15816 AN: 60316

GnomAD4 genome AF: 0.226 AC: 34454 AN: 152140 Hom.: 4935 Cov.: 32 AF XY: 0.223 AC XY: 16558 AN XY: 74382

African (AFR) AF: 0.0795 AC: 3304 AN: 41542

American (AMR) AF: 0.222 AC: 3385 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.278 AC: 965 AN: 3468

East Asian (EAS) AF: 0.0276 AC: 143 AN: 5178

South Asian (SAS) AF: 0.126 AC: 609 AN: 4832

European-Finnish (FIN) AF: 0.289 AC: 3055 AN: 10568

Middle Eastern (MID) AF: 0.248 AC: 73 AN: 294

European-Non Finnish (NFE) AF: 0.324 AC: 22052 AN: 67960

Other (OTH) AF: 0.228 AC: 481 AN: 2114

Alfa AF: 0.289 Hom.: 30277

Bravo AF: 0.214

TwinsUK AF: 0.324 AC: 1203

ALSPAC AF: 0.327 AC: 1261

ESP6500AA AF: 0.0921 AC: 406

ESP6500EA AF: 0.320 AC: 2754

ExAC AF: 0.232 AC: 28209

Asia WGS AF: 0.0900 AC: 318 AN: 3478

EpiCase AF: 0.323

EpiControl AF: 0.324

ClinVar

Significance: Benign

Submissions summary: Benign:31 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9 Other:1

Jun 24, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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

Mayo Clinic Laboratories, Mayo Clinic

Significance: 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

Aug 23, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as benign based on its high frequency in the general population (rs1799977, MAF >3%).

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Ile219Val variant is not expected to have clinical significance because this residue is not well conserved and the variant amino acid Val (valine) at position 219 is present in frog and zebrafish. In addition, this variant is listed in dbSNP as a common polymorphism (dbSNP#:rs1799977).

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

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

Colorectal cancer, hereditary nonpolyposis, type 2 Benign:5

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: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 20, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:5

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24595079, 15918206, 30998989, 28932927, 24728327, 27173243, 27153395, 7704024, 27487738, 9032648, 20336543, 23760103, 20981092, 9697702, 24689082, 22753075, 22949387, 21120944, 17594722, 11555625, 19371218, 22283331, 21239990, 11781295, 16083711, 21136174, 20149637, 19665066, 23403630, 16982745, 17510385, 12810663, 18547406, 19863800, 21615986, 23060557, 22703879, 20860725)

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Lynch syndrome Benign:4

Nov 15, 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%

Oct 02, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 10, 2025

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:3

Nov 04, 2014

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 10, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Nov 13, 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.

Lynch syndrome 1 Benign:2

Jul 24, 2014

Pathway Genomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 18, 2017

IntelligeneCG

Significance: Benign

Review Status: criteria provided, single submitter

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

Malignant tumor of breast Benign:1

Center of Medical Genetics and Primary Health Care

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.00042
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.46	N
REVEL	Uncertain	0.29
Sift	Benign	0.34	T
Sift4G	Benign	0.50	T
Polyphen		0.018	B
Vest4		0.057
MPC		0.075
ClinPred		0.0099	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.39
Mutation Taster		=89/11	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1799977; hg19: chr3-37053568; COSMIC: COSV51613800; COSMIC: COSV51613800;