MLH1c.2044_2045delUncertain significance

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Variant interpretation report

MLH1 c.2044_2045del, p.(Met682ValfsTer11)

NM_000249.4:c.2044_2045del NP_000240.1:p.(Met682ValfsTer11) 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): 6 Pathogenic
Pipeline record: 21 Aug 2026 · version 7.0.6

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): MLH1 c.2044_2045del (p.Met682ValfsTer11) is a frameshift deletion in exon 18 that introduces a premature termination codon at codon 693, upstream of codon 753, meeting PVS1 at very strong strength under the InSiGHT MLH1 specification.
PM2 (supporting): The variant is absent from gnomAD v2.1 and v4.1, meeting PM2 at supporting strength (allele frequency <0.00002).

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

MLH1 c.2044_2045del (p.Met682ValfsTer11) is a frameshift deletion in exon 18 that introduces a premature termination codon at codon 693, upstream of codon 753, meeting PVS1 at very strong strength under the InSiGHT MLH1 specification.

PM2Supporting

PM2 · supporting

The variant is absent from gnomAD v2.1 and v4.1, meeting PM2 at supporting strength (allele frequency <0.00002).

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

0.000 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

6 reported laboratory submissions

6 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

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

The variant is absent from gnomAD v2.1 and v4.1, meeting PM2 at supporting strength.

The variant has been reported in ClinVar as Pathogenic (6 clinical laboratories; ClinVar VariationID 237329) and has been observed in Hispanic families with Lynch syndrome.

No variant-specific functional, segregation, or tumor phenotype data were identified; PS3, PP1, and PP4 are not met, and all benign criteria are not met.

Met · 2

PVS1 Very strongMLH1 c.2044_2045del (p.Met682ValfsTer11) is a frameshift deletion in exon 18 that introduces a premature termination codon at codon 693, upstream of codon 753, meeting PVS1 at very strong strength under the InSiGHT MLH1 specification. Details ▾Hide ▴

Evidence considered

Frameshift deletion introducing PTC at codon 693 (p.Met682ValfsTer11)
before the codon 753 threshold defined by the InSiGHT MLH1 VCEP for PVS1_VeryStrong.
Loss-of-function is an established disease mechanism for MLH1 (Lynch syndrome
autosomal dominant)
gene context confirms PVS1 eligibility.
PMID 25389437 independently confirms the c.2044_2045 AT deletion in exon 18 causes a frameshift at p.682 with premature termination and a truncated MLH1 protein.

Sources

cspec ↗pvs1_variant_assessmentpvs1_gene_context

PM2 SupportingThe variant is absent from gnomAD v2.1 and v4.1, meeting PM2 at supporting strength (allele frequency <0.00002). Details ▾Hide ▴

Evidence considered

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

Sources

gnomad_v2 ↗gnomad_v4 ↗

Not met · 10 · evaluated, threshold not reached

PS2 No de novo observation with confirmed maternity/paternity was identified for this variant. Details ▾Hide ▴

Still missing

No de novo case reported for this variant.

PS3 No variant-specific functional assay or systematically characterized residue range includes this variant; available functional literature tests other MLH1 missense variants and does not characterize this position. Details ▾Hide ▴

Evidence considered

OncoKB labels the variant 'Likely Loss-of-function / Likely Oncogenic' but provides no primary variant-specific functional data.
Reviewed functional papers (PMID 11781295
10359802
12697830
16216036) are gene-level or test other MLH1 residues
none directly assays c.2044_2045del.

Still missing

No experimental functional characterization of this variant or a systematically assayed range containing codon 682.

Sources

oncokb ↗

PP1 No co-segregation data with a computed Bayes likelihood ratio is available for this variant. Details ▾Hide ▴

Still missing

No pedigree co-segregation analysis available.

PP4 No MSI-H tumor or MMR protein expression loss data specific to this variant is available in the reviewed abstracts. Details ▾Hide ▴

Still missing

No tumor MSI/IHC phenotype data specific to this variant.

BA1 The variant is absent from gnomAD and does not reach the BA1 allele frequency threshold (>=0.001). Details ▾Hide ▴

Evidence considered

Absent from gnomAD v4.1.

Sources

gnomad_v4 ↗

BS1 The variant is absent from gnomAD and does not reach the BS1 allele frequency threshold (0.01-0.1%). 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 an individual without CMMRD has been reported. Details ▾Hide ▴

Still missing

No co-occurrence (in trans) data available.

BS3 No functional evidence demonstrating normal/proficient MMR function for this variant is available. Details ▾Hide ▴

Still missing

No benign functional assay data for this variant.

BS4 No lack-of-co-segregation data is available for this variant. Details ▾Hide ▴

Still missing

No non-segregation pedigree data available.

BP5 No alternate molecular basis (MSS tumor, BRAF V600E, or MLH1 methylation) has been reported for this variant. Details ▾Hide ▴

Still missing

No tumor data demonstrating an alternate molecular basis.

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 splice-site variants; this is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

PS4 VCEPPS4 is not applicable under the InSiGHT MLH1 specification. Details ▾Hide ▴

No further detail was recorded.

PM1 VCEPPM1 is not applicable under the InSiGHT MLH1 specification. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped; recessive/CMMRD co-occurrence criterion, not applicable for this dominant Lynch syndrome frameshift assessment. Details ▾Hide ▴

No further detail was recorded.

PM4 VCEPPM4 is not applicable under the InSiGHT MLH1 specification. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to missense substitutions at a residue with a known pathogenic missense change; this is a frameshift deletion with no missense comparator. Details ▾Hide ▴

Evidence considered

pm5_candidates reports no eligible same-residue missense comparator
variant class is frameshift
not missense.

Sources

pm5_candidates

PM6 VCEPPM6 is not applicable under the InSiGHT MLH1 specification. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPPP2 is not applicable under the InSiGHT MLH1 specification. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APP3 (HCI prior or SpliceAI-based splice prediction) applies to missense or splice variants; this is a frameshift deletion with a SpliceAI max delta of 0.00. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.00 (no predicted splice impact).

Sources

spliceai ↗

PP5 VCEPPP5 is not applicable under the InSiGHT MLH1 specification, and the ClinVar record is 'criteria provided, single submitter' (not a 3-star expert panel). Details ▾Hide ▴

Evidence considered

ClinVar review status is 'criteria provided
single submitter' with no expert panel submission.

Sources

clinvar ↗

BP1 VCEPBP1 is not applicable under the InSiGHT MLH1 specification. Details ▾Hide ▴

No further detail was recorded.

BP2 VCEPBP2 is not applicable under the InSiGHT MLH1 specification (BS2 is used instead). Details ▾Hide ▴

No further detail was recorded.

BP3 VCEPBP3 is not applicable under the InSiGHT MLH1 specification (in-frame deletion in repetitive region); this is an out-of-frame deletion. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 (HCI prior or SpliceAI benign prediction) applies to missense, synonymous, or intronic variants; this is a frameshift deletion. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.00 (no predicted splice impact)
but BP4 is not applicable to frameshift variants.

Sources

spliceai ↗

BP6 VCEPBP6 is not applicable under the InSiGHT MLH1 specification, and the ClinVar record is 'criteria provided, single submitter' (not a 3-star expert panel). Details ▾Hide ▴

Evidence considered

ClinVar review status is 'criteria provided
single submitter' with no expert panel submission.

Sources

clinvar ↗

BP7 N/ABP7 applies to synonymous or intronic variants at/beyond the -21/+7 splice region; this is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 (de novo) is not used in this VCEP; de novo evidence is assessed under PS2, and no de novo data exist. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: MLH1
Transcript: NM_000249.4
Coding (HGVS c.): NM_000249.4:c.2044_2045del
Protein (HGVS p.): NP_000240.1:p.(Met682ValfsTer11)
GRCh38: chr3:37048956 CTA>C
GRCh37: chr3:37090447 CTA>C
ClinVar: 237329

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

-0.055

Pangolin splice gain

0.009

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

PP3 N/APP3 (HCI prior or SpliceAI-based splice prediction) applies to missense or splice variants; this is a frameshift deletion with a SpliceAI max delta of 0.00. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.00 (no predicted splice impact).

Sources

spliceai ↗

BP4 N/ABP4 (HCI prior or SpliceAI benign prediction) applies to missense, synonymous, or intronic variants; this is a frameshift deletion. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score = 0.00 (no predicted splice impact)
but BP4 is not applicable to frameshift variants.

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous or intronic variants at/beyond the -21/+7 splice region; this is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

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

7 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

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Casey G et al. · 2005

Evaluates conversion analysis for detecting germline MLH1/MSH2/MSH6 mutations in colorectal cancer patients. c.2044_2045del is not specifically identified in the abstract.
Does not name this variant
PMID 15713769 ↗
Different mutator phenotypes in Mlh1- versus Pms2-deficient mice.

Mouse study comparing mutator phenotypes of Mlh1- and Pms2-deficient strains; gene-level functional context only. c.2044_2045del is not assessed.
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 expression system. c.2044_2045del is not among the tested variants.
Does not name this variant
PMID 11781295 ↗
Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha.

Shows MLH1-PMS2 C-terminal dimerization regulates nuclear localization of MutLalpha. Gene/mechanism-level data; c.2044_2045del is not assessed.
Does not name this variant
PMID 12697830 ↗
Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining.

IHC study of MLH1/MSH2 expression in tumors from MMR mutation carriers. Gene-level; c.2044_2045del is not specifically identified.
Does not name this variant
PMID 16216036 ↗
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

Thompson BA et al. · 2014

InSiGHT 5-tiered classification of 2,360 MMR gene variants; c.2044_2045del is not specifically named in the abstract.
Does not name this variant
PMID 24362816 ↗
Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.

Consensus guidelines for genetic evaluation and management of Lynch syndrome; no variant-specific data.
Does not name this variant
PMID 25070057 ↗

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 6 Pathogenic 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 (6 clinical laboratories). (ClinVarID = 237329)

In silico

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

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.