About MLH3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MLH3 c.20T>A, p.(Val7Asp)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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 Not recorded. 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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_001040108.2:c.20T>A is absent from gnomAD v2.1 and v4.1 population databases, meeting the PM2 threshold for a variant with allele frequency below 0.1% in controls.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
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.
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
1 reported laboratory submissions
1 Uncertain significance.
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. MLH3, a DNA mismatch repair protein, is infrequently altered in cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV53136280, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 20 not met · 1 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001040108.2:c.20T>A (p.Val7Asp) is a missense variant in exon 2 of MLH3, a DNA mismatch repair gene associated with autosomal dominant Lynch syndrome and autosomal recessive polyposis predisposition.
This variant is absent from gnomAD v2.1 and v4.1 population databases, supporting PM2 at a supporting strength level.
Multiple computational predictors do not support a deleterious effect: REVEL score is 0.384 (intermediate), BayesDel is −0.281 (benign-leaning), and SpliceAI predicts no splice impact (max delta 0.00). PP3 is not met.
The variant has been reported once in ClinVar as Uncertain significance by a single clinical laboratory (Ambry Genetics; Variation ID 1785889); no pathogenic or benign consensus exists.
No variant-specific functional studies, case-control data, cosegregation evidence, or de novo observations were identified for this variant in the available evidence sources.
The PVS1 criterion is not applicable as this is a missense change (p.Val7Asp) that does not meet the ClinGen SVI PVS1 null-variant criteria (PMC6185798).
The variant has been observed once in a somatic cancer context (COSMIC COSV53136280), which is not directly informative for germline pathogenicity classification.
No criteria match.
Met · 1
PM2 SupportingNM_001040108.2:c.20T>A is absent from gnomAD v2.1 and v4.1 population databases, meeting the PM2 threshold for a variant with allele frequency below 0.1% in controls. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- absent from gnomAD v4.1 (exomes+genomes).
Sources
Not met · 20 · evaluated, threshold not reached
PS1 No established pathogenic variant with the same amino acid change (p.Val7Asp) at this residue has been identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- ClinVar contains no pathogenic classification at residue 7 with a Val7Asp change.
Still missing
- No same-residue comparator with known pathogenicity identified.
Sources
PS2 No de novo occurrence of NM_001040108.2:c.20T>A has been reported in a patient with confirmed parental relationships. Details ▾Hide ▴
Evidence considered
- No de novo data available in evidence sources
- ClinVar
- or literature.
Still missing
- No de novo testing or trio data available.
PS3 No well-established functional studies demonstrate a deleterious effect of p.Val7Asp on MLH3 protein function. OncoKB did not identify variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional studies identified.
Still missing
- No functional assay data for p.Val7Asp.
Sources
PS4 No case-control or cohort data demonstrate enrichment of NM_001040108.2:c.20T>A in affected individuals compared to controls. Details ▾Hide ▴
Evidence considered
- No case-control or prevalence data for this variant.
Still missing
- No affected-vs-control comparison data available.
PM1 The variant lies at residue 7 in MLH3, which is not within a statistically significant cancer hotspot and does not fall within a well-characterized critical functional domain without benign variation. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue not statistically significant
- no critical domain evidence.
Still missing
- No domain-level constraint analysis available.
PM6 No assumed de novo without paternity/maternity confirmation has been reported for NM_001040108.2:c.20T>A. Details ▾Hide ▴
Evidence considered
- No de novo assertions found in ClinVar or literature.
Still missing
- No de novo data available.
PP1 No cosegregation data with disease has been reported for this variant in affected families. Details ▾Hide ▴
Evidence considered
- No cosegregation analysis available.
Still missing
- No family studies with this variant.
PP3 Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.384 (below typical pathogenic threshold), BayesDel score -0.281 (benign-leaning), and SpliceAI max delta 0.00 (no predicted splice impact). Details ▾Hide ▴
Evidence considered
- REVEL: 0.384
- BayesDel: -0.281
- SpliceAI max delta: 0.00.
Sources
PP4 No specific phenotype or family history data are available for the individual harboring NM_001040108.2:c.20T>A to assess phenotypic specificity for MLH3-associated disease. Details ▾Hide ▴
Evidence considered
- No phenotype or family history data provided.
Still missing
- Patient phenotype and family history not available.
PP5 No reputable source (e.g., expert panel, clinical laboratory consensus) reports NM_001040108.2:c.20T>A as pathogenic. The sole ClinVar submission classifies it as Uncertain significance. Details ▾Hide ▴
BA1 The variant is absent from gnomAD v2.1 and v4.1; allele frequency does not exceed the 1% threshold for BA1. Details ▾Hide ▴
BS1 The variant is absent from gnomAD v2.1 and v4.1; allele frequency does not exceed the 0.3% threshold for BS1. Details ▾Hide ▴
BS2 The variant has not been observed in a homozygous state in healthy adults, nor has it been observed at a frequency inconsistent with MLH3-associated disease penetrance. Details ▾Hide ▴
Evidence considered
- No homozygotes observed
- absent from population databases.
Sources
BS3 No well-established functional studies demonstrate a neutral or non-deleterious effect of p.Val7Asp on MLH3 protein function. OncoKB did not identify variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional studies found.
Still missing
- No functional assay data for p.Val7Asp.
Sources
BS4 No non-segregation data with disease in affected families is available for NM_001040108.2:c.20T>A. Details ▾Hide ▴
Evidence considered
- No segregation or non-segregation data available.
Still missing
- No family-based segregation studies.
BP2 No evidence that NM_001040108.2:c.20T>A has been observed in trans with a known pathogenic MLH3 variant in the context of a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No trans-phase observations with pathogenic MLH3 variant.
Still missing
- No phase-resolved genotyping data available.
BP4 Computational evidence is mixed and does not consistently support a non-deleterious effect: BayesDel predicts benign (-0.281), but REVEL is intermediate (0.384) and SpliceAI is neutral (max delta 0.00). Multiple lines of computational evidence do not converge on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.384 (intermediate)
- BayesDel: -0.281 (benign-leaning)
- SpliceAI: 0.00 (neutral).
Sources
BP5 No case has been identified where NM_001040108.2:c.20T>A was found in a patient with an alternate molecular basis for MLH3-associated disease. Details ▾Hide ▴
Evidence considered
- No alternate-molecular-basis observations available.
Still missing
- No cases with dual diagnoses reported.
BP6 No reputable source reports NM_001040108.2:c.20T>A as benign or likely benign. ClinVar classification is Uncertain significance (single submitter). Details ▾Hide ▴
PS5 ClinVar classification is Uncertain significance (single submitter, Ambry Genetics); no reputable source asserts pathogenicity for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS
- 1 clinical laboratory (Ambry Genetics)
- criteria provided
- single submitter.
Sources
Not assessed · 1 · no assessment recorded
PP2 Insufficient gene-level constraint data (missense Z-score, benign missense rate) available to determine whether MLH3 has a low rate of benign missense variation that would qualify for PP2. HCI prior lookup did not return a score for MLH3. Details ▾Hide ▴
Evidence considered
- HCI prior not found for MLH3
- gnomAD missense constraint metrics not retrieved.
Still missing
- Gene-level missense constraint data (Z-score) needed for PP2 assessment.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001040108.2:c.20T>A is a missense variant (p.Val7Asp) that does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant at codon 7
- not a null variant
- variant bucket classified as 'other'.
Sources
PM5 N/ANo same-residue missense comparator variant with a confirmed pathogenic classification could be identified. Automated PM5 candidate harvesting was unable to confirm eligible comparators. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned 0 same-residue comparator variants.
BP1 N/ABoth missense and truncating variants in MLH3 are known to be associated with Lynch syndrome and polyposis predisposition; MLH3 is not a gene for which primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- MLH3 literature supports both missense and truncating pathogenic mechanisms.
BP7 N/ANM_001040108.2:c.20T>A is a missense variant (p.Val7Asp), not a synonymous variant. SpliceAI predicts no splice impact (max delta 0.00), but BP7 is reserved for synonymous variants without predicted splice effect. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 criteria not applicable to non-synonymous variants.
Sources
Identifiers
- Gene
- MLH3
- Transcript
- NM_001040108.2
- Coding (HGVS c.)
- NM_001040108.2:c.20T>A
- Protein (HGVS p.)
- NP_001035197.1:p.(Val7Asp)
- GRCh38
- chr14:75049636 A>T
- GRCh37
- chr14:75516339 A>T
- ClinVar
- 1785889
- COSMIC
- COSV53136280
Gene diagram
Every interpreted variant in MLH3, mapped onto the exon structure of NM_001040108.2. Select a row to find it on the plot.
MLH3NM_001040108.2
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 MLH3
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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
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.384
- BayesDel
- -0.281
How the predictions were used
PP3 Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.384 (below typical pathogenic threshold), BayesDel score -0.281 (benign-leaning), and SpliceAI max delta 0.00 (no predicted splice impact). Details ▾Hide ▴
Evidence considered
- REVEL: 0.384
- BayesDel: -0.281
- SpliceAI max delta: 0.00.
Sources
BP4 Computational evidence is mixed and does not consistently support a non-deleterious effect: BayesDel predicts benign (-0.281), but REVEL is intermediate (0.384) and SpliceAI is neutral (max delta 0.00). Multiple lines of computational evidence do not converge on a benign prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.384 (intermediate)
- BayesDel: -0.281 (benign-leaning)
- SpliceAI: 0.00 (neutral).
Sources
BP7 N/ANM_001040108.2:c.20T>A is a missense variant (p.Val7Asp), not a synonymous variant. SpliceAI predicts no splice impact (max delta 0.00), but BP7 is reserved for synonymous variants without predicted splice effect. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 criteria not applicable to non-synonymous variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.384. BayesDel score = -0.280993.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
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
1 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 ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1785889/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/14-75516339-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr14-75049636-A-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001040108.2%3Ac.2…
- OncoKB ↗www.oncokb.org/gene/MLH3/V7D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=136504670
- Cancer hotspots ↗www.cancerhotspots.org/
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.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1785889)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.384. BayesDel score = -0.280993.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MLH3, a DNA mismatch repair protein, is infrequently altered in cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53136280, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.