Genetic Information

Gene & Transcript Details

Gene
MLH1
Transcript
NM_000249.4 MANE Select
Total Exons
—
Reference Sequence
NC_000003.11
Alternative Transcripts
IDStatusDetails
NM_000249.4 MANE Select 2494 nt | 31–2301
NM_000249.3 RefSeq Select 2662 nt | 199–2469
NM_000249.2 Alternative 2524 nt | 61–2331

Variant Details

HGVS Notation
NM_000249.4:c.1682A>G
Protein Change
Y561C
Location
Exon 15 (Exon 15 of )
15
5'Exon Structure3'
Functional Consequence
Loss of Function
Alternate Identifiers
—

Clinical & Population Data

Population Frequency

gnomAD
Global Frequency
0.00319 in 100,000
Extremely Rare
ACMG Criteria Applied PM2
This variant is absent or extremely rare in population databases (PM2 criteria applies).

ClinVar

Open
Classification
Uncertain Significance (VUS)
2 publications
Publications List
PMID: 10612827

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 561 of the MLH1 protein (p.Tyr561Cys). This variant is present in population databases (no rsID available, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of MLH1-related conditions (PMID: 10612827, 21520333). ClinVar contains an entry for this variant (Variation ID: 483536). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MLH1 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Clinical Statement

"This variant has been reported in ClinVar as Uncertain significance (10 clinical laboratories) and as Uncertain Significance (1 clinical laboratories)."

COSMIC Somatic Evidence

Open
COSMIC ID
Recurrence
0 occurrences
PM1 Criteria
Not Applied
COSMIC Database Preview
COSMIC Preview
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Functional Impact & Domains

Functional Domain

Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain.
Related Variants in This Domain
No evidence of other pathogenic variants at this position in gene MLH1.

Functional Studies & Therapeutic Relevance

Functional Summary

Error in OpenAI Consolidation. OncoKB: MLH1Y561CMLH1Y561CSomaticNCBI Gene:4292|Show additional gene information Variant OverviewMLH1, a DNA mismatch repair protein, is recurrently altered by deletion and mutation in various cancer types.The MLH1 Y561C mutation has not specifically been reviewed by the OncoKB team, and therefore its biological significance is unknown. JAX-CKB: No results found

Database Previews
OncoKB
OncoKB Preview
JAX-CKB
JAX-CKB Preview

Click on previews to view full database entries. External databases may require institutional access.

Computational Analysis

Pathogenicity Predictions

SpliceAI
Predictor Consensus
Mixed/VUS
PP3 Applied
No
REVEL Score
0.0
Threshold: ≥0.75 = PP3 applied

SpliceAI Scores

Window: ±500bp
Effect Type Score Position
- Acceptor Loss (AL) 0.0 43 bp
- Donor Loss (DL) 0.0 49 bp
+ Acceptor Gain (AG) 0.01 -9 bp
+ Donor Gain (DG) 0.0 436 bp
High impact (≥0.5) Medium impact (0.2-0.49) Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria (VCEP Specific)

Filter Criteria:
PM2

PM2 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)

BP4

BP4 (Unknown (Pre-LLM))

From pre-LLM assessment (LLM Failed)