chr3-37012077-A-T

Variant names:

• chr3-37012077-A-T
• rs1799977
• NM_000249.4:c.655A>T
• MLH1 p.Ile219Phe

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO6_Supporting

The NM_000249.4(MLH1):c.655A>T (p.Ile219Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene MLH1 is a tumor suppressor gene (CancerMine: 10 TSG, 4 oncogene, 3 driver citations). The gene MLH1 is a known oncogene (CancerMine: 10 TSG, 4 oncogene, 3 driver citations). The gene MLH1 is a cancer driver gene (CancerMine: 10 TSG, 4 oncogene, 3 driver citations). The variant allele was found at a cumulative frequency of 0.00000137 (AC=2) in the gnomAD database across 1,460,796 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000003. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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); p.I219V: Benign (ClinVar VariationId 36557, 3 stars)

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MLH1 NM_000249.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.05
• Publications: 124 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 ACGS-UK Somatic Oncogenicity v2025

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: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000000, AC = 2 — absent/extremely rare (O3 moderate [+2])
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect

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>T p.Ile219Phe	missense	Exon 8 of 19	Prot: NP_000240.1 UniProt:
	MLH1 NM_001354628.2		c.655A>T p.Ile219Phe	missense	Exon 8 of 18	Prot: NP_001341557.1 UniProt:
	MLH1 NM_001354629.2		c.556A>T p.Ile186Phe	missense	Exon 7 of 18	Prot: NP_001341558.1 UniProt:

MLH1 NM_000249.4

MANE Select

HGVSc / HGVSpc.655A>Tp.Ile219Phe

Exon rankExon 8 of 19

missense

Prot: NP_000240.1UniProt: P40692-1

MLH1 NM_001354628.2

HGVSc / HGVSpc.655A>Tp.Ile219Phe

Exon rankExon 8 of 18

missense

Prot: NP_001341557.1UniProt: A0A087WX20

MLH1 NM_001354629.2

HGVSc / HGVSpc.556A>Tp.Ile186Phe

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>T p.Ile219Phe	missense	Exon 8 of 19	Prot: ENSP00000231790.3 UniProt:
	MLH1 ENST00000456676.7	TSL:1	c.655A>T p.Ile219Phe	missense	Exon 8 of 17	Prot: ENSP00000416687.3 UniProt:
	MLH1 ENST00000413740.2	TSL:1	c.655A>T p.Ile219Phe	missense	Exon 8 of 15	Prot: ENSP00000416476.2 UniProt:

MLH1 ENST00000231790.8

TSL:1MANE Select

HGVSc / HGVSpc.655A>Tp.Ile219Phe

Exon rankExon 8 of 19

missense

Prot: ENSP00000231790.3UniProt: P40692-1

MLH1 ENST00000456676.7

TSL:1

HGVSc / HGVSpc.655A>Tp.Ile219Phe

Exon rankExon 8 of 17

missense

Prot: ENSP00000416687.3UniProt: H0Y818

MLH1 ENST00000413740.2

TSL:1

HGVSc / HGVSpc.655A>Tp.Ile219Phe

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 5 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 exome	AF: 0.00000137	AC:2	Hom:0	AN:1460796	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32
TOPMed (Bravo)	AF: 0.00000756	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:31907	AN:710128	Cov:

Showing 5 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	20
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.93	D
FuncVEP CTI	Pathogenic	0.51
GPN-Star LLR	N/A	-8.7
GPN-Star score	N/A	8.7
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.56	D
Mutation Taster	N/A	34/66	disease causing
MutationAssessor	Pathogenic	3.1	M
PhyloP100	Benign	2.0
popEVE	Benign	-3.5
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.3	D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0060	D
Varity_R	N/A	0.65
VESM-3B	Benign	-11

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
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;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar