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MLH1c.1433A>GNot classified
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Variant interpretation report

MLH1 c.1433A>G, p.(Asp478Gly)

NM_000249.3:c.1433A>G NP_000240.1:p.(Asp478Gly) View identifiers
Classification
Not classified

Variant description:

No variant summary was recorded for this case.

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

Not classified yet.Select a step to read what it means.

In plain language

Gene-level background from the recorded interpretation.

About MLH1

No gene-level summary was recorded for this case.

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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v4.1, meeting the VCEP PM2_supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles). It is also absent from gnomAD v2.1 and gnomAD-Canada v1.0.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

The HCI prior probability for pathogenicity is 0.0146, which is <0.11, meeting the VCEP BP4_Supporting threshold for missense variants. Multiple in silico tools predict a benign impact: REVEL score 0.604 (below typical pathogenic threshold), BayesDel 0.161, and SpliceAI max delta 0.00 (no predicted splicing effect).

Recorded classification: Not classified

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 Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting; maps to Uncertain Significance - Conflicting Evidence.

02The sources

Evidence at a glance

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

SpliceAI score
0.000 maximum delta

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

Applied · BP4 → SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

2 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MLH1, a DNA mismatch repair protein, is recurrently altered by deletion and mutation in various cancer types.

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.

29 criteria with recorded statuses: 2 met · 7 not met · 6 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PM2_supporting met: variant is absent from gnomAD v4.1, meeting the VCEP allele frequency threshold of <0.00002 (<1 in 50,000 alleles).

BP4_supporting met: HCI prior probability for pathogenicity is 0.0146 (<0.11), consistent with a benign in silico prediction. REVEL score 0.604 and BayesDel 0.161 also favor a benign interpretation.

PP3 not met: HCI prior 0.0146 does not reach the PP3 supporting threshold of >0.68. SpliceAI delta 0.00 does not indicate splicing impact.

PS3 not met: no variant-specific functional data from calibrated MMR assays available. OncoKB reports Unknown Oncogenic Effect.

PVS1 not applicable: this is a missense variant and does not meet any VCEP PVS1 rule criteria.

Overall, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, yielding insufficient evidence for classification. Defaults to Uncertain Significance per ACMG/AMP 2015 framework.

Met · 2

PM2 SupportingThis variant is absent from gnomAD v4.1, meeting the VCEP PM2_supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles). It is also absent from gnomAD v2.1 and gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1 (AF <0.00002)
  • Absent from gnomAD v2.1
  • Absent from gnomAD-Canada v1.0
Sources
gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗
BP4 SupportingThe HCI prior probability for pathogenicity is 0.0146, which is <0.11, meeting the VCEP BP4_Supporting threshold for missense variants. Multiple in silico tools predict a benign impact: REVEL score 0.604 (below typical pathogenic threshold), BayesDel 0.161, and SpliceAI max delta 0.00 (no predicted splicing effect). Details ▾Hide ▴
Evidence considered
  • HCI prior probability: 0.0146 (threshold: <0.11 for BP4_Supporting)
  • SpliceAI max delta: 0.00
  • REVEL: 0.604
  • BayesDel: 0.161
Sources
hci_priorspliceai ↗revelbayesdel

Not met · 7 · evaluated, threshold not reached

PS1 No different nucleotide change encoding the same amino acid substitution (p.Asp478Gly) has been classified as Pathogenic or Likely Pathogenic by the InSiGHT MMR VCEP. The VCEP pilot variants spreadsheet does not list any variant at codon 478. Details ▾Hide ▴
Evidence considered
  • VCEP pilot variants spreadsheet reviewed
  • no p.Asp478Gly or codon 478 comparator identified
Sources
vcep_vcep_pilot_variants_mmr
PS3 No variant-specific functional data from calibrated MMR assays exists. OncoKB reports Unknown Oncogenic Effect with no reviewed functional evidence. The VCEP pilot variants spreadsheet does not include this variant, and no functional odds for pathogenicity are available from the calibrated assay documentation. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific reviewed functional evidence
  • VCEP functional assay SVI documentation reviewed
  • variant not listed in any calibrated assay
  • VCEP pilot variants spreadsheet: variant not present
Still missing
  • No functional data from calibrated MMR assays for this variant
Sources
oncokb ↗vcep_functional_assay_svi_documentation_mmrvcep_vcep_pilot_variants_mmr
PM5 No pathogenic or likely pathogenic missense variant at the same amino acid residue (Asp478) has been classified by the InSiGHT MMR VCEP. The PM5 candidate search found zero same-residue comparator variants. VCEP PM5 requires an existing P/LP missense classification at the same residue by this VCEP and supporting PP3 evidence. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: 0 same-residue candidates found
  • VCEP pilot variants spreadsheet: no codon 478 variant listed
Sources
pm5_candidatesvcep_vcep_pilot_variants_mmr
PP3 The HCI prior probability for pathogenicity is 0.0146, which does not meet the VCEP PP3 thresholds (>0.68 for supporting, >0.81 for moderate). SpliceAI predicts no splicing impact (max delta score 0.00), which does not meet the ≥0.2 threshold for non-canonical splice site variants. REVEL score is 0.604 and BayesDel is 0.161, but the VCEP PP3 rules rely on HCI priors and SpliceAI. Details ▾Hide ▴
Evidence considered
  • HCI prior probability: 0.0146 (thresholds: >0.68 supporting
  • >0.81 moderate)
  • SpliceAI max delta: 0.00 (threshold ≥0.2 for non-canonical splice)
  • REVEL: 0.604
  • BayesDel: 0.161
Sources
hci_priorspliceai ↗revelbayesdel
BA1 This variant is absent from gnomAD v4.1, which does not meet the VCEP BA1 threshold of gnomAD v4 Grpmax filtering allele frequency ≥0.001 (0.1%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1 (threshold: Grpmax FAF ≥0.001)
Sources
gnomad_v4 ↗
BS1 This variant is absent from gnomAD v4.1, which does not meet the VCEP BS1 threshold of gnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001 (0.01-0.1%). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1 (threshold: Grpmax FAF ≥0.0001 and <0.001)
Sources
gnomad_v4 ↗
BS3 No functional data from calibrated MMR assays demonstrating proficient function exists for this variant. VCEP BS3 requires calibrated functional odds for pathogenicity ≤0.05 (strong) or >0.05 and ≤0.48 (supporting), or variant-specific proficient function per the MMR assay flowchart. Details ▾Hide ▴
Evidence considered
  • No functional data in VCEP calibrated assay documentation
  • OncoKB: Unknown Oncogenic Effect
  • no benign functional evidence
Still missing
  • No functional data from calibrated MMR assays
Sources
vcep_functional_assay_svi_documentation_mmroncokb ↗

Not assessed · 6 · no assessment recorded

PS2 No de novo observations reported for this variant. VCEP PS2 requires de novo points based on confirmed parentage. Details ▾Hide ▴
Still missing
  • No de novo data available
PP1 No co-segregation data available for this variant. VCEP PP1 requires Bayes likelihood ratios from pedigrees with combined analysis. Details ▾Hide ▴
Still missing
  • No co-segregation data available
PP4 No tumor MSI or IHC data available. VCEP PP4 requires specific counts of MSI-H CRC/endometrial tumors with loss of MMR protein expression consistent with the variant location, with MLH1 promoter methylation excluded. Details ▾Hide ▴
Still missing
  • No tumor MSI or MMR IHC data available
BS2 No data on co-occurrence in trans with a known pathogenic variant in the same gene in a CRC patient after age 45 without CMMRD features. Details ▾Hide ▴
Still missing
  • No co-occurrence/phase data available
BS4 No co-segregation data available. VCEP BS4 requires lack of co-segregation with disease in pedigrees with combined Bayes likelihood ratio. Details ▾Hide ▴
Still missing
  • No co-segregation data available
BP5 No tumor phenotype data available. VCEP BP5 requires specific counts of CRC/endometrial tumors with MSS and/or no loss of MMR protein expression, or BRAF V600E/MLH1 methylation in relevant tumors. Details ▾Hide ▴
Still missing
  • No tumor phenotype data available
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense substitution (c.1433A>G, p.Asp478Gly); does not meet any VCEP PVS1 rule criteria, which are restricted to nonsense/frameshift variants introducing PTC at or before codon 753, large genomic alterations, IVS±1/±2 splice variants, initiation codon variants, or confirmed mRNA splicing aberrations. Details ▾Hide ▴
Evidence considered
  • VCEP MLH1 PVS1 rules v2.0.0: missense variants are not eligible for PVS1
  • PVS1 variant assessment confirms variant_bucket='other'
  • not in null-variant categories
Sources
pvs1_gene_contextpvs1_variant_assessment
PS4 VCEPPS4 is marked Not Applicable by the InSiGHT MMR VCEP specification (version 2.0.0). Details ▾Hide ▴
Evidence considered
  • VCEP specification: PS4 applicability = Not Applicable
Sources
cspec ↗
PM1 VCEPPM1 is marked Not Applicable by the InSiGHT MMR VCEP specification (version 2.0.0). Details ▾Hide ▴
Evidence considered
  • VCEP specification: PM1 applicability = Not Applicable
Sources
cspec ↗
PM3 N/APM3 requires observation in trans with a pathogenic variant; no such data has been provided for this case. Trivially not applicable per case skip directive. Details ▾Hide ▴

No further detail was recorded.

PM4 VCEPPM4 applies only to non-frameshift in-frame deletions/insertions and stop-loss variants; this is a missense substitution. Trivially not applicable. Details ▾Hide ▴

No further detail was recorded.

PM6 VCEPPM6 is marked Not Applicable by the InSiGHT MMR VCEP specification (version 2.0.0). Details ▾Hide ▴
Evidence considered
  • VCEP specification: PM6 applicability = Not Applicable
Sources
cspec ↗
PP2 VCEPPP2 is marked Not Applicable by the InSiGHT MMR VCEP specification (version 2.0.0). Details ▾Hide ▴
Evidence considered
  • VCEP specification: PP2 applicability = Not Applicable
Sources
cspec ↗
PP5 VCEPPP5 is marked Not Applicable by the InSiGHT MMR VCEP specification (version 2.0.0), per ClinGen SVI VCEP Review Committee recommendation. Details ▾Hide ▴
Evidence considered
  • VCEP specification: PP5 applicability = Not Applicable
Sources
cspec ↗
BP1 VCEPBP1 is marked Not Applicable by the InSiGHT MMR VCEP specification (version 2.0.0). Details ▾Hide ▴
Evidence considered
  • VCEP specification: BP1 applicability = Not Applicable
Sources
cspec ↗
BP2 VCEPBP2 is marked Not Applicable by the InSiGHT MMR VCEP specification (version 2.0.0). Details ▾Hide ▴
Evidence considered
  • VCEP specification: BP2 applicability = Not Applicable
Sources
cspec ↗
BP3 VCEPBP3 is marked Not Applicable by the InSiGHT MMR VCEP specification (version 2.0.0). Details ▾Hide ▴
Evidence considered
  • VCEP specification: BP3 applicability = Not Applicable
Sources
cspec ↗
BP6 VCEPBP6 is marked Not Applicable by the InSiGHT MMR VCEP specification (version 2.0.0), per ClinGen SVI VCEP Review Committee recommendation. Details ▾Hide ▴
Evidence considered
  • VCEP specification: BP6 applicability = Not Applicable
Sources
cspec ↗
BP7 N/ABP7 applies only to synonymous (silent) and intronic variants at or beyond -21/+7. This is a missense substitution (c.1433A>G, p.Asp478Gly) and is not eligible. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous or intronic
PS5 N/APS5 is not included in the InSiGHT MMR VCEP specification (version 2.0.0) criteria list. Details ▾Hide ▴
Evidence considered
  • PS5 is not a criterion in the ClinGen InSiGHT MMR VCEP v2.0.0 specification
Sources
cspec ↗

Identifiers

Gene
MLH1
Transcript
NM_000249.3
Coding (HGVS c.)
NM_000249.3:c.1433A>G
Protein (HGVS p.)
NP_000240.1:p.(Asp478Gly)
GRCh38
chr3:37028807 A>G
GRCh37
chr3:37070298 A>G
ClinVar
418302

Gene diagram

Every interpreted variant in MLH1, mapped onto the exon structure of NM_000249.3. Select a row to find it on the plot.

MLH1NM_000249.3
Fetching transcript structure from UCSC…
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 -23 bp
0.000
SpliceAI acceptor gainat -19 bp
0.000
SpliceAI donor lossat +47 bp
0.000
SpliceAI donor gainat -1 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.604
BayesDel
0.161

How the predictions were used

BP4 SupportingThe HCI prior probability for pathogenicity is 0.0146, which is <0.11, meeting the VCEP BP4_Supporting threshold for missense variants. Multiple in silico tools predict a benign impact: REVEL score 0.604 (below typical pathogenic threshold), BayesDel 0.161, and SpliceAI max delta 0.00 (no predicted splicing effect). Details ▾Hide ▴
Evidence considered
  • HCI prior probability: 0.0146 (threshold: <0.11 for BP4_Supporting)
  • SpliceAI max delta: 0.00
  • REVEL: 0.604
  • BayesDel: 0.161
Sources
hci_priorspliceai ↗revelbayesdel
PP3 The HCI prior probability for pathogenicity is 0.0146, which does not meet the VCEP PP3 thresholds (>0.68 for supporting, >0.81 for moderate). SpliceAI predicts no splicing impact (max delta score 0.00), which does not meet the ≥0.2 threshold for non-canonical splice site variants. REVEL score is 0.604 and BayesDel is 0.161, but the VCEP PP3 rules rely on HCI priors and SpliceAI. Details ▾Hide ▴
Evidence considered
  • HCI prior probability: 0.0146 (thresholds: >0.68 supporting
  • >0.81 moderate)
  • SpliceAI max delta: 0.00 (threshold ≥0.2 for non-canonical splice)
  • REVEL: 0.604
  • BayesDel: 0.161
Sources
hci_priorspliceai ↗revelbayesdel
BP7 N/ABP7 applies only to synonymous (silent) and intronic variants at or beyond -21/+7. This is a missense substitution (c.1433A>G, p.Asp478Gly) and is not eligible. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous or intronic

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.604. BayesDel score = 0.160558. HCI prior probability for pathogenicity = 0.0146. MAPP score = 8.56. Custom PP2 score = 0.027.

1 paper record 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

  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    Nykamp K et al. · 2017
    Describes the Sherloc variant classification framework as a refinement of ACMG-AMP guidelines. NM_000249.3:c.1433A>G (p.Asp478Gly) was not identified in this paper.
    Does not name this variant
    PMID 28492532 ↗

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 2 Uncertain significance 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 Uncertain significance (2 clinical laboratories). (ClinVarID = 418302)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.604. BayesDel score = 0.160558. HCI prior probability for pathogenicity = 0.0146. MAPP score = 8.56. Custom PP2 score = 0.027.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MLH1, a DNA mismatch repair protein, is recurrently altered by deletion and mutation in various cancer types.

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.