NM_000249.4:c.655A>G

Variant names:

• chr3-37012077-A-G
• rs1799977
• NM_000249.4:c.655A>G
• MLH1 p.Ile219Val

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -16 classification points (ACMG Germline Pathogenicity v2019). BA1BP6_Very_Strong

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 cumulative frequency of 0.284 (AC=457,531) in the gnomAD database across 1,610,830 control chromosomes, including 71,241 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.323. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.I219L: Benign (ClinVar VariationId 90305, 3 stars); p.I219M: Uncertain_significance (ClinVar VariationId 489902, 1 star); p.I219T: Uncertain_significance (ClinVar VariationId 483584, 2 stars); p.I219V: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 920597) This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• 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: 2 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: ClinGen, G2P, Orphanet
• Lynch syndrome 2

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

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

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

Classification according to ACMG Germline Pathogenicity v2019

Specifications for MLH1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Benign. The variant received -16 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	BP6Reputable source reports benign		ClinVar ≥3 stars benign — very strong (BP6); ClinVar submissions overwhelmingly benign (≥10 total, ≥80% B/LB, <10% P/LP) — strong (BP6, count-based); ClinVar germline classification: Benign/Likely Benign, 3 star(s). ClinVar submissions strongly and reliably favor benignity (31/31 total B/LB).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.3228 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	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	Prot: NP_000240.1 UniProt:
	MLH1 NM_001354628.2		c.655A>G p.Ile219Val	missense	Exon 8 of 18	Prot: NP_001341557.1 UniProt:
	MLH1 NM_001354629.2		c.556A>G p.Ile186Val	missense	Exon 7 of 18	Prot: NP_001341558.1 UniProt:

MLH1 NM_000249.4

MANE Select

HGVSc / HGVSpc.655A>Gp.Ile219Val

Exon rankExon 8 of 19

missense

Prot: NP_000240.1UniProt: P40692-1

MLH1 NM_001354628.2

HGVSc / HGVSpc.655A>Gp.Ile219Val

Exon rankExon 8 of 18

missense

Prot: NP_001341557.1UniProt: A0A087WX20

MLH1 NM_001354629.2

HGVSc / HGVSpc.556A>Gp.Ile186Val

Exon rankExon 7 of 18

missense

Prot: NP_001341558.1UniProt: A0AAQ5BGZ2

Ensembl Transcripts

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

MLH1 ENST00000231790.8

TSL:1MANE Select

HGVSc / HGVSpc.655A>Gp.Ile219Val

Exon rankExon 8 of 19

missense

Prot: ENSP00000231790.3UniProt: P40692-1

MLH1 ENST00000456676.7

TSL:1

HGVSc / HGVSpc.655A>Gp.Ile219Val

Exon rankExon 8 of 17

missense

Prot: ENSP00000416687.3UniProt: H0Y818

MLH1 ENST00000413740.2

TSL:1

HGVSc / HGVSpc.655A>Gp.Ile219Val

Exon rankExon 8 of 15

missense

Prot: ENSP00000416476.2UniProt: H0Y806

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.227	AC:34464	Hom:4934	AN:152022	Cov:32
GnomAD2 exomes	AF: 0.233	AC:58439	Hom:	AN:251064	Cov:
GnomAD4 exome	AF: 0.290	AC:423077	Hom:66306	AN:1458690	Cov:32
GnomAD4 genome	AF: 0.226	AC:34454	Hom:4935	AN:152140	Cov:32
TOPMed (Bravo)	AF: 0.214	AC:56701	Hom:7717	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.285	AC:202655	Hom:31907	AN:710128	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.270	AC:633	Hom:110	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.0227	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.373	AC:112	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.243	AC:3160	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.0900	AC:318	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.0290	AC:208	Hom:	AN:7234	Cov:
Qatari Genome	AF: 0.260	AC:523	Hom:	AN:2010	Cov:
Turkish Variome	AF: 0.267	AC:1794	Hom:268	AN:6714	Cov:
UK10K	AF: 0.326	AC:2464	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.0181	AC:162	Hom:2	AN:8960	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.314 *	3490	11110	0.319 *	5610	17608
BipEx(Bipolar disorder (including schizoaffective))	0.327	9283	28420	0.319	9211	28844
Epi25(Epilepsy)	0.273	11435	41958	0.273	18275	66888
SCHEMA(Schizophrenia)	0.216	29098	134924	0.243	54505	224524

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	9	not specified (10)
-	-	5	Colorectal cancer, hereditary nonpolyposis, type 2 (5)
-	-	5	not provided (5)
-	-	4	Lynch syndrome (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	2	Lynch syndrome 1 (2)
-	-	1	Hereditary nonpolyposis colorectal neoplasms (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	Muir-Torré syndrome (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
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
FuncVEP CTI	Benign	0.00052
GPN-Star LLR	N/A	-3.9
GPN-Star score	N/A	3.9
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	89/11	polymorphism (auto)
MutationAssessor	Benign	1.0	L
PhyloP100	Benign	2.0
popEVE	Benign	-3.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.46	N
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Uncertain	0.29
Sift	Benign	0.34	T
Sift4G	Benign	0.50	T
Varity_R	N/A	0.063
VESM-3B	Benign	-6.2

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs1799977;

hg19: chr3-37053568;

COSMIC: COSV51613800;

COSMIC: COSV51613800;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar