chr3-37017508-CGT-GGC

Variant names:

• chr3-37017508-CGT-GGC
• NM_000249.4:c.793_795delCGTinsGGC
• MLH1 p.Arg265Gly

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+6 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 6 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO5_ModerateO6_SupportingO7_Supporting

The NM_000249.4(MLH1):c.793_795delCGTinsGGC (p.Arg265Gly) variant causes a missense, splice region change. 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). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.59). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R265V: Pathogenic (ClinVar VariationId 619508, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R265H: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 90381); p.R265L: Uncertain_significance (ClinVar VariationId 1928288, 2 stars); p.R265= (synonymous): Likely_benign (ClinVar VariationId 491730, 2 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: MLH1 NM_000249.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.59
• Publications: 0 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: Likely_pathogenic. The variant received 6 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 = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O5Same location/impact as known oncogenic		Same AA change as established oncogenic variant (or germline P/LP in TSG) — Moderate (O5); Beware: this change may impact splicing rather than at the amino acid/protein level; ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: true | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer does not indicate an oncogenic effect; O6 not met via missense path; Splice-region variant — splicing algorithms predict an impact on splicing; supports O6
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 4 pathogenic, 3 benign (OR vs. background: 6.4); No cancerhotspots.org splice hotspot hit at this position

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.793_795delCGTinsGGC p.Arg265Gly	missensesplice_region	N/A	Prot: NP_000240.1 UniProt:
	MLH1 NM_001354628.2		c.793_795delCGTinsGGC p.Arg265Gly	missensesplice_region	N/A	Prot: NP_001341557.1 UniProt:
	MLH1 NM_001354629.2		c.694_696delCGTinsGGC p.Arg232Gly	missensesplice_region	N/A	Prot: NP_001341558.1 UniProt:

MLH1 NM_000249.4

MANE Select

HGVSc / HGVSpc.793_795delCGTinsGGCp.Arg265Gly

Exon rankN/A

missensesplice_region

Prot: NP_000240.1UniProt: P40692-1

MLH1 NM_001354628.2

HGVSc / HGVSpc.793_795delCGTinsGGCp.Arg265Gly

Exon rankN/A

missensesplice_region

Prot: NP_001341557.1UniProt: A0A087WX20

MLH1 NM_001354629.2

HGVSc / HGVSpc.694_696delCGTinsGGCp.Arg232Gly

Exon rankN/A

missensesplice_region

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.793_795delCGTinsGGC p.Arg265Gly	missensesplice_region	N/A	Prot: ENSP00000231790.3 UniProt:
	MLH1 ENST00000456676.7	TSL:1	c.793_795delCGTinsGGC p.Arg265Gly	missensesplice_region	N/A	Prot: ENSP00000416687.3 UniProt:
	MLH1 ENST00000413740.2	TSL:1	c.793_795delCGTinsGGC p.Arg265Gly	missensesplice_region	N/A	Prot: ENSP00000416476.2 UniProt:

MLH1 ENST00000231790.8

TSL:1MANE Select

HGVSc / HGVSpc.793_795delCGTinsGGCp.Arg265Gly

Exon rankN/A

missensesplice_region

Prot: ENSP00000231790.3UniProt: P40692-1

MLH1 ENST00000456676.7

TSL:1

HGVSc / HGVSpc.793_795delCGTinsGGCp.Arg265Gly

Exon rankN/A

missensesplice_region

Prot: ENSP00000416687.3UniProt: H0Y818

MLH1 ENST00000413740.2

TSL:1

HGVSc / HGVSpc.793_795delCGTinsGGCp.Arg265Gly

Exon rankN/A

missensesplice_region

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 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	9.6

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

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

hg19: chr3-37058999;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar