MLH1c.549T>AUncertain significance

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Variant interpretation report

MLH1 c.549T>A, p.(Tyr183Ter)

NM_000249.4:c.549T>A NP_000240.1:p.(Tyr183Ter) View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

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) · 1 supporting (pathogenic)
Expert rules: ClinGen MLH1 VCEP v2.0
Other laboratories (ClinVar): 1 Likely benign
Pipeline record: 21 Aug 2026 · version 7.0.6

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): NM_000249.4:c.549T>A is a nonsense variant that introduces a premature termination codon at codon 183 (p.Tyr183Ter), well before the MLH1 cutoff of codon 753, and loss of function is an established disease mechanism for MLH1 in Lynch syndrome; this satisfies PVS1 at very strong strength per the InSiGHT MLH1 VCEP.
PM2 (supporting): The variant is absent from gnomAD v2.1 and v4.1, meeting the InSiGHT MLH1 VCEP PM2_Supporting threshold of an allele frequency below 0.00002 (fewer than 1 in 50,000 alleles).

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. 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: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PVS1Very strong

PVS1 · very strong

NM_000249.4:c.549T>A is a nonsense variant that introduces a premature termination codon at codon 183 (p.Tyr183Ter), well before the MLH1 cutoff of codon 753, and loss of function is an established disease mechanism for MLH1 in Lynch syndrome; this satisfies PVS1 at very strong strength per the InSiGHT MLH1 VCEP.

PM2Supporting

PM2 · supporting

The variant is absent from gnomAD v2.1 and v4.1, meeting the InSiGHT MLH1 VCEP PM2_Supporting threshold of an allele frequency below 0.00002 (fewer than 1 in 50,000 alleles).

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MLH1 Version 2.0 v2.0 criteria-combination framework was evaluated deterministically with applied criteria: PVS1 very strong, PM2 supporting; no rule matched the adjudicated criteria.

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

0.014 maximum delta

Recorded SpliceAI maximum delta score: 0.014. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

1 reported laboratory submissions

1 Likely benign.

Context only 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, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 10 not met · 0 not assessed · 17 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000249.4:c.549T>A is a nonsense variant predicted to introduce a premature termination codon at codon 183 (p.Tyr183Ter) in MLH1, a gene in which loss of function is an established cause of Lynch syndrome.

Per the InSiGHT MLH1 VCEP, a nonsense/frameshift variant introducing a premature termination codon at or before codon 753 meets PVS1 at very strong strength.

This variant has not been observed in gnomAD v2.1 or v4.1, meeting the InSiGHT MLH1 VCEP PM2_Supporting criterion.

No ClinVar expert-panel classification exists for this variant; the only retrieved ClinVar record was a mismatched c.1272T>A entry and therefore carries no weight for PP5/BP6 (which are not applicable in this VCEP).

PVS1 at very strong strength is independently sufficient for a Pathogenic classification under the InSiGHT MLH1 VCEP combination rules (Rule 1: one very strong pathogenic criterion).

Met · 2

PVS1 Very strongNM_000249.4:c.549T>A is a nonsense variant that introduces a premature termination codon at codon 183 (p.Tyr183Ter), well before the MLH1 cutoff of codon 753, and loss of function is an established disease mechanism for MLH1 in Lynch syndrome; this satisfies PVS1 at very strong strength per the InSiGHT MLH1 VCEP. Details ▾Hide ▴

Evidence considered

Nonsense (stop-gain) variant p.Tyr183Ter in exon 7
Premature termination codon at codon 183
before the codon 753 threshold
Loss-of-function is the established disease mechanism for MLH1 (Lynch syndrome)

Sources

cspec ↗pvs1_gene_contextpvs1_variant_assessment

PM2 SupportingThe variant is absent from gnomAD v2.1 and v4.1, meeting the InSiGHT MLH1 VCEP PM2_Supporting threshold of an allele frequency below 0.00002 (fewer than 1 in 50,000 alleles). Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (exome)
Absent from gnomAD v4.1 (exome)

Sources

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

Not met · 10 · evaluated, threshold not reached

PS2 No de novo occurrence of this variant with confirmed maternity and paternity has been reported in the available evidence. Details ▾Hide ▴

Still missing

No de novo report available for this variant

PS3 No calibrated functional assay or variant-specific functional study of p.Tyr183Ter was identified; the reviewed publications describe MLH1 function at the gene or domain level only. Details ▾Hide ▴

Evidence considered

Reviewed publications are gene-level functional studies (mouse knockout
dimerization
and a panel of other missense variants)
none tested p.Tyr183Ter

Still missing

No variant-specific functional data for p.Tyr183Ter

Sources

PMID:10359802 ↗PMID:11781295 ↗PMID:12697830 ↗

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

Still missing

No co-segregation or pedigree data available

PP4 No tumor microsatellite instability (MSI) or MMR protein immunohistochemistry data are available for this variant to support PP4. Details ▾Hide ▴

Still missing

No tumor MSI or MMR protein IHC data available

BA1 The variant is absent from gnomAD, so it does not meet the BA1 allele frequency threshold (>= 0.001 in gnomAD v4). Details ▾Hide ▴

Evidence considered

Absent from gnomAD v4.1

Sources

gnomad_v4 ↗

BS1 The variant is absent from gnomAD, so it does not meet the BS1 allele frequency threshold (>= 0.0001 and < 0.001 in gnomAD v4). Details ▾Hide ▴

Evidence considered

Absent from gnomAD v4.1

Sources

gnomad_v4 ↗

BS2 No observation of this variant in trans with a known pathogenic MLH1 variant in a patient without CMMRD has been reported. Details ▾Hide ▴

Still missing

No co-occurrence (in trans) data available

BS3 No functional assay demonstrating normal (proficient) protein function for p.Tyr183Ter was identified; the reviewed publications are gene-level studies only. Details ▾Hide ▴

Still missing

No variant-specific functional data demonstrating normal function

Sources

PMID:10359802 ↗PMID:11781295 ↗PMID:12697830 ↗

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

Still missing

No segregation data available

BP5 No tumor data (MSS tumors, no loss of MMR protein expression, BRAF V600E, or MLH1 promoter methylation) are available to support BP5. Details ▾Hide ▴

Still missing

No tumor MSS/BRAF V600E/MLH1 methylation data available

Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 applies to missense substitutions encoding the same amino acid change or to variants at the same non-canonical splice nucleotide; this is a nonsense variant, so PS1 does not apply. Details ▾Hide ▴

Sources

cspec ↗

PS4 VCEPPS4 is not utilized for MMR variant classification by the InSiGHT MLH1 VCEP because tumor IHC data (PP4) is used instead of proband counting. Details ▾Hide ▴

Sources

cspec ↗

PM1 VCEPPM1 is not applicable for MLH1 in the InSiGHT VCEP because there are no recognized mutational hotspots suitable for classification. Details ▾Hide ▴

Sources

cspec ↗

PM3 N/APM3 requires biallelic in trans co-occurrence with a pathogenic variant in a recessive (CMMRD) context, which is not the setting for this dominant Lynch syndrome case. Details ▾Hide ▴

No further detail was recorded.

PM4 VCEPPM4 applies to protein length changes from in-frame insertions/deletions or stop-loss; this is a nonsense (stop-gain) substitution and PM4 is not used in the InSiGHT MLH1 VCEP. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a missense change at a residue where a different missense change is pathogenic; this is a nonsense variant, so PM5 does not apply. Details ▾Hide ▴

Sources

cspec ↗

PM6 VCEPPM6 (assumed de novo without confirmation of parentage) is not applicable in the InSiGHT MLH1 VCEP; PS2 is used instead. Details ▾Hide ▴

Sources

cspec ↗

PP2 VCEPPP2 (missense variant in a gene with a low rate of benign missense variation) is not applicable in the InSiGHT MLH1 VCEP. Details ▾Hide ▴

Sources

cspec ↗

PP3 N/APP3 in the InSiGHT MLH1 VCEP applies only to missense variants (HCI prior) and non-canonical splice variants (SpliceAI delta >= 0.2); this is a nonsense variant and SpliceAI predicts no splicing impact (max delta score 0.014). Details ▾Hide ▴

Evidence considered

HCI prior not applicable (variant is nonsense
not missense)
SpliceAI max delta score 0.014 (no predicted splice impact)

Sources

cspec ↗spliceai ↗

PP5 VCEPPP5 is not applicable in the InSiGHT MLH1 VCEP; additionally, no ClinVar expert-panel classification exists for this variant (the only retrieved ClinVar record was a mismatched c.1272T>A entry). Details ▾Hide ▴

Sources

cspec ↗clinvar ↗

BP1 VCEPBP1 (missense variant in a gene where primarily truncating variants cause disease) is not applicable in the InSiGHT MLH1 VCEP. Details ▾Hide ▴

Sources

cspec ↗

BP2 VCEPBP2 is not applicable in the InSiGHT MLH1 VCEP; BS2 is used instead. Details ▾Hide ▴

Sources

cspec ↗

BP3 VCEPBP3 applies to in-frame deletions/insertions in a repetitive region; this is a single-nucleotide nonsense substitution. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 in the InSiGHT MLH1 VCEP applies only to missense variants (HCI prior < 0.11) and intronic/synonymous variants (SpliceAI <= 0.1); this is a nonsense coding variant, so BP4 does not apply. Details ▾Hide ▴

Sources

cspec ↗spliceai ↗

BP6 VCEPBP6 is not applicable in the InSiGHT MLH1 VCEP; additionally, no ClinVar expert-panel classification exists for this variant. Details ▾Hide ▴

Sources

cspec ↗clinvar ↗

BP7 N/ABP7 applies only to synonymous or intronic variants; this is a nonsense (stop-gain) coding variant. Details ▾Hide ▴

Sources

cspec ↗

PS5 N/APS5 is not defined in the InSiGHT MLH1 VCEP framework (not a standard criterion for this gene), so it cannot be applied. Details ▾Hide ▴

Sources

cspec ↗

Identifiers

Gene: MLH1
Transcript: NM_000249.4
Coding (HGVS c.): NM_000249.4:c.549T>A
Protein (HGVS p.): NP_000240.1:p.(Tyr183Ter)
GRCh38: chr3:37011823 T>A
GRCh37: chr3:37053314 T>A
ClinVar: 3873425

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

SpliceAI acceptor lossat +192 bp

0.014

SpliceAI acceptor gainat +5 bp

0.001

SpliceAI donor lossat +39 bp

0.004

SpliceAI donor gainat -4 bp

0.001

Pangolin splice lossmagnitude shown

-0.032

Pangolin splice gain

0.005

Other predictors

REVEL: 0.273
BayesDel: 0.660

How the predictions were used

Evidence considered

HCI prior not applicable (variant is nonsense
not missense)
SpliceAI max delta score 0.014 (no predicted splice impact)

Sources

cspec ↗spliceai ↗

Sources

cspec ↗spliceai ↗

BP7 N/ABP7 applies only to synonymous or intronic variants; this is a nonsense (stop-gain) coding variant. Details ▾Hide ▴

Sources

cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.273. BayesDel score = 0.66.

6 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.

Describes microsatellite mutation spectra in Mlh1- and Pms2-deficient mice; a gene-level knockout study that does not analyze the human c.549T>A variant.
Does not name this variant
PMID 10359802 ↗
Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system.

Functional analysis of specific hMLH1 missense variants (T117M, V185G, R217C, G244D, R265C, V326A, K618T) in a human 293T expression system; p.Tyr183Ter was not among the variants tested.
Does not name this variant
PMID 11781295 ↗
Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha.

Studies MLH1/PMS2 dimerization and its regulation of MutLalpha nuclear localization; a gene-level mechanistic study without variant-specific analysis.
Does not name this variant
PMID 12697830 ↗
Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Evaluates conversion analysis for mutation detection in MLH1 and MSH2 in colorectal cancer patients; does not report the specific c.549T>A variant.
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.

Compares MLH1/MSH2 immunohistochemical staining in tumors from mutation carriers; a gene-level study without variant-specific data for c.549T>A.
Does not name this variant
PMID 16216036 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.

Hampel H et al. · 2015

ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment; does not report this specific variant.
Does not name this variant
PMID 25394175 ↗

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 0.014 Open source ↗

ClinVar 1 Likely benign 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

Error retrieving ClinVar entry.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.273. 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.