MLH1c.1875T>GPathogenic

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Variant interpretation report

MLH1 c.1875T>G, p.(Tyr625Ter)

NM_000249.4:c.1875T>G NP_000240.1:p.(Tyr625Ter) View identifiers

Classification

Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About MLH1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 2 supporting (pathogenic)
Expert rules: ClinGen MLH1 VCEP v2.0.0
Pipeline record: 8 Jul 2026 · version 7.0.1

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): NM_000249.4:c.1875T>G is a nonsense variant introducing a premature termination codon at position 625 (p.Tyr625Ter), which is before codon 753 in MLH1, satisfying the InSiGHT VCEP v2.0.0 criterion for PVS1 at Very Strong strength.
PM2 (supporting): NM_000249.4:c.1875T>G is absent from gnomAD v4.1 (0 alleles), meeting the InSiGHT VCEP threshold of <0.00002 (fewer than 1 in 50,000 alleles) for PM2_Supporting.
PP5 (supporting): Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is ClinGen MLH1 VCEP v2.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 3 Benign evidence criteria: 0

Pathogenic criteria applied · 3

PVS1Very strong

PVS1 · very strong

NM_000249.4:c.1875T>G is a nonsense variant introducing a premature termination codon at position 625 (p.Tyr625Ter), which is before codon 753 in MLH1, satisfying the InSiGHT VCEP v2.0.0 criterion for PVS1 at Very Strong strength.

PM2Supporting

PM2 · supporting

NM_000249.4:c.1875T>G is absent from gnomAD v4.1 (0 alleles), meeting the InSiGHT VCEP threshold of <0.00002 (fewer than 1 in 50,000 alleles) for PM2_Supporting.

PP5Supporting

PP5 · supporting

Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MLH1 Version 2.0.0 v2.0.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM2 supporting, PP5 supporting; maps to Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded. ClinVar API review status: reviewed by expert panel.

Applied · PP5 → ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen MLH1 VCEP v2.0.0, with the data and sources behind each one.

26 criteria with recorded statuses: 3 met · 10 not met · 0 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000249.4:c.1875T>G (p.Tyr625Ter) is a nonsense variant in MLH1 introducing a premature termination codon at position 625, upstream of the VCEP threshold at codon 753, meeting PVS1 at Very Strong strength.

The variant is absent from gnomAD v4.1, v2.1, and gnomAD-Canada, meeting PM2 at Supporting strength under the InSiGHT VCEP threshold of fewer than 1 in 50,000 alleles.

This variant has been classified as Pathogenic by the International Society for Gastrointestinal Hereditary Tumours (InSiGHT) expert panel in ClinVar (ClinVar ID: 89914).

Met · 3

PVS1 Very strongNM_000249.4:c.1875T>G is a nonsense variant introducing a premature termination codon at position 625 (p.Tyr625Ter), which is before codon 753 in MLH1, satisfying the InSiGHT VCEP v2.0.0 criterion for PVS1 at Very Strong strength. Details ▾Hide ▴

Evidence considered

Nonsense variant at codon 625
upstream of the VCEP threshold at codon 753
MLH1 loss-of-function is an established disease mechanism for Lynch syndrome per VCEP

Sources

gnomad_v4 ↗gnomad_v2 ↗cspec ↗

PM2 SupportingNM_000249.4:c.1875T>G is absent from gnomAD v4.1 (0 alleles), meeting the InSiGHT VCEP threshold of <0.00002 (fewer than 1 in 50,000 alleles) for PM2_Supporting. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v4.1 (0 alleles)
Absent from gnomAD v2.1 (0 alleles)
Absent from gnomAD-Canada v1.0 (0 alleles)

Sources

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

PP5 SupportingExpert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic. Details ▾Hide ▴

Evidence considered

ClinVar expert panel classification

Sources

clinvar ↗

Not met · 10 · evaluated, threshold not reached

PS2 No de novo observations are available for this variant. PS2 requires de novo occurrence data with confirmed parentage. Details ▾Hide ▴

Still missing

No de novo data available in case evidence or literature

PS3 No variant-specific functional assay data were identified in the VCEP functional assay spreadsheet or the reviewed literature for NM_000249.4:c.1875T>G. Details ▾Hide ▴

Still missing

No functional assay data for this variant in VCEP calibrated assay spreadsheet or literature

PP1 No co-segregation data are available for this variant. Details ▾Hide ▴

Still missing

No co-segregation data available

PP4 No tumor phenotype data (MSI status, IHC for MMR protein expression) are available in the case evidence for this variant. Details ▾Hide ▴

Still missing

No tumor MSI/IHC phenotype data available in the case evidence

BA1 The variant is absent from gnomAD v4.1. The InSiGHT VCEP BA1 threshold requires gnomAD v4 Grpmax filtering allele frequency >= 0.001 (0.1%), which is not met. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 0.0 (0 alleles)

Sources

gnomad_v4 ↗

BS1 The variant is absent from gnomAD v4.1. The InSiGHT VCEP BS1 threshold requires gnomAD v4 Grpmax filtering allele frequency >= 0.0001 and < 0.001 (0.01-0.1%), which is not met. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 0.0 (0 alleles)

Sources

gnomad_v4 ↗

BS2 No evidence of co-occurrence in trans with a known pathogenic variant in MLH1 in a patient with colorectal cancer after age 45 and without CMMRD features. Details ▾Hide ▴

Still missing

No co-occurrence data available

BS3 No variant-specific functional assay data demonstrating proficient MMR function are available. The variant was not found in the VCEP calibrated functional assay spreadsheet. Details ▾Hide ▴

Still missing

No functional data demonstrating benign effect

BS4 No segregation data demonstrating lack of co-segregation with disease are available for this variant. Details ▾Hide ▴

Still missing

No segregation data available

BP5 No tumor phenotype data (MSS status, MMR protein expression, BRAF V600E, or MLH1 methylation status) are available in the case evidence. Details ▾Hide ▴

Still missing

No tumor phenotype data available

Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 per the InSiGHT VCEP applies to missense substitutions encoding the same amino acid change as a known pathogenic variant, or splice variants at the same non-canonical nucleotide. NM_000249.4:c.1875T>G is a nonsense variant. Details ▾Hide ▴

No further detail was recorded.

PS4 VCEPPS4 is marked Not Applicable by the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴

No further detail was recorded.

PM1 VCEPPM1 is marked Not Applicable by the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 per the InSiGHT VCEP applies to missense changes at an amino acid residue where a different missense change was classified as Pathogenic/Likely Pathogenic. NM_000249.4:c.1875T>G is a nonsense variant. Details ▾Hide ▴

No further detail was recorded.

PM6 VCEPPM6 is marked Not Applicable by the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPPP2 is marked Not Applicable by the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APP3 per the InSiGHT VCEP applies to missense variants via HCI prior probability or to non-canonical splice variants via SpliceAI. NM_000249.4:c.1875T>G is a nonsense variant with no splice impact (SpliceAI max delta = 0.00). Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.00 (no predicted splice impact)
Variant is not in the HCI-PRIORS-MLH1 missense lookup table (nonsense variant)

Sources

spliceai ↗

BP1 VCEPBP1 is marked Not Applicable by the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴

No further detail was recorded.

BP2 VCEPBP2 is marked Not Applicable by the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 per the InSiGHT VCEP applies to missense variants via HCI prior probability <0.11 or to intronic/synonymous variants via SpliceAI delta <= 0.1. NM_000249.4:c.1875T>G is a nonsense variant. Details ▾Hide ▴

Evidence considered

Variant is not in the HCI-PRIORS-MLH1 missense lookup table
SpliceAI max delta = 0.00 (not applicable to nonsense)

Sources

spliceai ↗

BP6 VCEPBP6 is marked Not Applicable by the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 per the InSiGHT VCEP applies to synonymous or intronic variants at or beyond -21/+7. NM_000249.4:c.1875T>G is a nonsense variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not defined in the InSiGHT MLH1 VCEP v2.0.0 specification; PP5 (which addresses similar evidence) is explicitly Not Applicable in this framework. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: MLH1
Transcript: NM_000249.4
Coding (HGVS c.): NM_000249.4:c.1875T>G
Protein (HGVS p.): NP_000240.1:p.(Tyr625Ter)
GRCh38: chr3:37047662 T>G
GRCh37: chr3:37089153 T>G
ClinVar: 918529, 89914, 1781767

Gene diagram

Every interpreted variant in MLH1, mapped onto the exon structure of NM_000249.4. Select a row to find it on the plot.

MLH1NM_000249.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in MLH1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.060

Pangolin splice gain

0.010

Other predictors

REVEL: 0.366
BayesDel: 0.660

How the predictions were used

Evidence considered

SpliceAI max delta score = 0.00 (no predicted splice impact)
Variant is not in the HCI-PRIORS-MLH1 missense lookup table (nonsense variant)

Sources

spliceai ↗

Evidence considered

Variant is not in the HCI-PRIORS-MLH1 missense lookup table
SpliceAI max delta = 0.00 (not applicable to nonsense)

Sources

spliceai ↗

BP7 N/ABP7 per the InSiGHT VCEP applies to synonymous or intronic variants at or beyond -21/+7. NM_000249.4:c.1875T>G is a nonsense variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.366. BayesDel score = 0.66.

8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

Different mutator phenotypes in Mlh1- versus Pms2-deficient mice.

Reports on microsatellite mutation spectra in Mlh1- versus Pms2-deficient mice. NM_000249.4:c.1875T>G was not identified in this paper.
Does not name this variant
PMID 10359802 ↗
Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system.

Functional analysis of MLH1 missense variants (T117M, V185G, R217C, G244D, R265C, V326A, K618T) in a human 293T expression system. NM_000249.4:c.1875T>G (p.Tyr625Ter) was not among the variants studied.
Does not name this variant
PMID 11781295 ↗
Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha.

Demonstrates that C-terminal dimerization of MLH1 and PMS2 is required for nuclear localization of MutLalpha. NM_000249.4:c.1875T>G was not identified in this paper.
Does not name this variant
PMID 12697830 ↗
Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Compares conversion analysis with DNA sequencing for MLH1 and MSH2 mutation detection in colorectal cancer patients. NM_000249.4:c.1875T>G was not identified in this paper.
Does not name this variant
PMID 15713769 ↗
Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining.

Reports IHC results for MSH2 and MLH1 in MSI-H tumors from HNPCC mutation carriers, including 44 MLH1 pathogenic mutation carriers. NM_000249.4:c.1875T>G was not individually identified in this paper.
Does not name this variant
PMID 16216036 ↗
American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.

Lu KH et al. · 2014

ASCO expert statement providing guidance on collection and use of cancer family history for oncology providers. NM_000249.4:c.1875T>G was not identified in this paper.
Does not name this variant
PMID 24493721 ↗
Lynch Syndrome: A Primer for Urologists and Panel Recommendations.

Mork M et al. · 2015

Review article on Lynch syndrome for urologists, discussing UTUC risk and diagnostic pathways. NM_000249.4:c.1875T>G was not identified in this paper.
Does not name this variant
PMID 25711197 ↗
American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.

ASCO policy statement update on genetic and genomic testing for cancer susceptibility. NM_000249.4:c.1875T>G was not identified in this paper.
Does not name this variant
PMID 26324357 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel). (ClinVarID = 89914)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.366. BayesDel score = 0.66.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.