Classification rationale

PVS1PM2 VUS

MLH1 c.2044_2045del frameshift

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.¹ The variant is absent from gnomAD v2.1 and v4.1, meeting PM2 at supporting strength.² 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.³ 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.

PVS1 + PM2 → VUS

1 cspec ↗pvs1_variant_assessment

2 gnomad_v2 ↗gnomad_v4 ↗

3 clinvar ↗

Gene diagram · NM_000249.4 · variants mapped to exon structure

MLH1 NM_000249.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 10 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

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.

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

cspec ↗

✓

PM2 supporting Pathogenic

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

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

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 10 not met · 0 not assessed

Pathogenic

PS2 No de novo observation with confirmed maternity/paternity was identified 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.

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

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

Benign

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

BS1 The variant is absent from gnomAD and does not reach the BS1 allele frequency threshold (0.01-0.1%).

BS2 No observation of this variant in trans with a known pathogenic MLH1 variant in an individual without CMMRD has been reported.

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

BS4 No lack-of-co-segregation data is available for this variant.

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

N/A · 16 PS1 · PS4 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP3 · PP5 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories). (ClinVarID = 237329)

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Likely Oncogenic

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

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

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

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

15713769 ↗ Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer. ONCOKB

10359802 ↗ Different mutator phenotypes in Mlh1- versus Pms2-deficient mice. ONCOKB

11781295 ↗ Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. ONCOKB

12697830 ↗ Dimerization of MLH1 and PMS2 limits nuclear localization of MutLalpha. ONCOKB

16216036 ↗ Tumours from MSH2 mutation carriers show loss of MSH2 expression but many tumours from MLH1 mutation carriers exhibit weak positive MLH1 staining. ONCOKB

24362816 ↗ Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. CLINVAR

25070057 ↗ Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer. CLINVAR