About MLH3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MLH3 c.1910G>A, p.(Arg637His)
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: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
Population frequency is below the 0.1% rarity threshold used for generic ACMG review. The variant is present at 0.00425% in gnomAD v2.1 and 0.00149% in gnomAD v4.1, with no homozygotes in either dataset, and it is absent from gnomAD-Canada v1.0.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple computational findings support no deleterious effect. REVEL is low at 0.103, BayesDel is negative at -0.485573, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
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 moderate, BP4 supporting; combination = 1 moderate + 1 supporting benign, which maps to VUS because the evidence is conflicting.
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
24 / 1,614,096 alleles
gnomAD v4.1: 24 / 1,614,096 alleles. Recorded AF 1.4869e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.24809e-05; MAF= 0.00425%, 12/282480 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000228758; MAF= 0.02288%, 7/30600 alleles, homozygotes = 0); grpmax FAF= 0.00010661.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
2 reported laboratory submissions
2 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
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV53152155, n = 2 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.
28 criteria with recorded statuses: 2 met · 4 not met · 15 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The MLH3 c.1910G>A (p.Arg637His, p.R637H) variant has been reported in ClinVar, where current submissions classify it as a variant of uncertain significance.
This variant is rare in population databases, with a total allele frequency of 0.00425% in gnomAD v2.1 and 0.00149% in gnomAD v4.1, and it is absent from gnomAD-Canada v1.0.
Available computational evidence does not support a damaging effect: REVEL is 0.103, BayesDel is -0.485573, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.
No criteria match.
Met · 2
PM2 ModeratePopulation frequency is below the 0.1% rarity threshold used for generic ACMG review. The variant is present at 0.00425% in gnomAD v2.1 and 0.00149% in gnomAD v4.1, with no homozygotes in either dataset, and it is absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Rule
generic ACMG rarity threshold
Evidence considered
- gnomAD v2.1 total AF 4.24809e-05 (12/282480)
- 0 homozygotes.
- gnomAD v4.1 total AF 1.4869e-05 (24/1614096)
- Absent from gnomAD-Canada v1.0.
Sources
BP4 SupportingMultiple computational findings support no deleterious effect. REVEL is low at 0.103, BayesDel is negative at -0.485573, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Rule
ACMG/AMP BP4
Evidence considered
- REVEL 0.103 supports a benign missense prediction.
- BayesDel -0.485573 supports a benign prediction.
- SpliceAI max delta 0.00 argues against splice disruption.
Sources
Not met · 4 · evaluated, threshold not reached
PM1 This variant has not been identified in a well-established functional domain or statistically significant hotspot, and Cancer Hotspots did not show a significant hotspot signal at residue R637. Details ▾Hide ▴
Rule
ACMG/AMP PM1
Evidence considered
- No hotspot row was found for MLH3 R637.
Still missing
- A gene-specific critical-domain framework was not available.
Sources
PP3 Available computational evidence does not support a damaging effect. REVEL is low at 0.103, BayesDel is negative at -0.485573, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Rule
ACMG/AMP PP3
Evidence considered
- REVEL 0.103.
- BayesDel -0.485573.
- SpliceAI max delta 0.00.
Sources
BA1 Population frequency does not meet the benign stand-alone threshold of greater than 1%. The highest observed population frequency is 0.02288% in gnomAD v2.1 South Asian samples, which is far below 1%. Details ▾Hide ▴
Rule
generic benign frequency threshold
Evidence considered
- Highest observed subpopulation AF in gnomAD v2.1 is 0.000228758 (0.02288%).
- Highest observed subpopulation AF in gnomAD v4.1 is 0.000164962 (0.01650%).
Sources
BS1 Population frequency does not exceed the benign strong threshold of greater than 0.3%. The highest observed population frequency is 0.02288% in gnomAD v2.1 South Asian samples, which is below 0.3%. Details ▾Hide ▴
Rule
generic benign frequency threshold
Evidence considered
- gnomAD v2.1 highest subpopulation AF 0.000228758 (0.02288%).
- gnomAD v4.1 highest subpopulation AF 0.000164962 (0.01650%).
Sources
Not assessed · 15 · no assessment recorded
PS1 No evidence was identified that a different nucleotide change causing the same Arg637His protein effect has already been established as pathogenic or likely pathogenic. Details ▾Hide ▴
Rule
ACMG/AMP PS1
Evidence considered
- ClinVar record for this exact variant was reviewed.
Still missing
- No validated pathogenic same-amino-acid comparator was identified.
Sources
PS2 No confirmed de novo occurrence data were identified for this variant. Details ▾Hide ▴
Rule
ACMG/AMP PS2
Evidence considered
- No de novo evidence was present in the reviewed materials.
Still missing
- Parental testing or verified de novo case data were not available.
Sources
PS3 No published well-established functional study demonstrating a damaging effect of this specific variant was identified. Details ▾Hide ▴
Rule
ACMG/AMP PS3
Evidence considered
- No variant-specific reviewed functional evidence was identified.
Still missing
- Variant-specific functional assay data were not available.
Sources
PS4 No case-control enrichment data or multiple independent affected observations sufficient to show increased prevalence in affected individuals were identified for this variant. Details ▾Hide ▴
Rule
ACMG/AMP PS4
Evidence considered
- ClinVar shows two uncertain-significance submissions without expert-panel review.
- Literature triage did not identify usable variant-specific enrichment evidence.
Still missing
- Published enrichment or multiple well-documented affected cases were not available.
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context. Details ▾Hide ▴
Rule
ACMG/AMP PM3
Evidence considered
- No trans observations were present in the reviewed materials.
Still missing
- Phase information and second-allele data were not available.
Sources
PM6 No assumed de novo occurrence data were identified for this variant. Details ▾Hide ▴
Rule
ACMG/AMP PM6
Evidence considered
- No de novo observations were present in the reviewed materials.
Still missing
- Case-level parental data were not available.
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Rule
ACMG/AMP PP1
Evidence considered
- No segregation evidence was present in the reviewed materials.
Still missing
- Pedigree-based segregation evidence was not available.
Sources
PP2 Available evidence does not establish that MLH3 missense variation in general is a common mechanism of disease with sufficiently low benign missense background to support PP2. Details ▾Hide ▴
Rule
ACMG/AMP PP2
Evidence considered
- No gene-specific PP2 rule was available.
Still missing
- A validated gene-specific missense constraint framework was not available.
Sources
final_classification_framework
PP4 No phenotype, family history, or tumor-feature evidence specific enough to support a highly characteristic disease presentation was identified for this variant. Details ▾Hide ▴
Rule
ACMG/AMP PP4
Evidence considered
- No case-specific phenotype details sufficient for PP4 were present.
Still missing
- Detailed clinical phenotype and tumor correlation data were not available.
Sources
BS2 No evidence was identified showing this variant in healthy adults in a context sufficient to establish BS2. Details ▾Hide ▴
Rule
ACMG/AMP BS2
Evidence considered
- No homozygotes were observed in gnomAD v2.1 or v4.1
- but this alone is not sufficient for BS2.
Still missing
- Validated unaffected-carrier data were not available.
Sources
BS3 No well-established functional study demonstrating normal or near-normal function for this specific variant was identified. Details ▾Hide ▴
Rule
ACMG/AMP BS3
Evidence considered
- No variant-specific reviewed functional evidence was identified.
Still missing
- Variant-specific benign functional assay data were not available.
Sources
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Rule
ACMG/AMP BS4
Evidence considered
- No family-based segregation evidence was present in the reviewed materials.
Still missing
- Family segregation studies were not available.
Sources
BP1 Available evidence does not establish that missense variation in MLH3 is a clearly low-risk mechanism relative to truncating variants, so BP1 was not applied. Details ▾Hide ▴
Rule
ACMG/AMP BP1
Evidence considered
- No gene-specific BP1 rule was available.
Still missing
- A validated gene-specific BP1 framework was not available.
Sources
final_classification_framework
BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant. Details ▾Hide ▴
Rule
ACMG/AMP BP2
Evidence considered
- No informative co-occurrence data were present in the reviewed materials.
Still missing
- Phase and co-occurrence data were not available.
Sources
BP5 No alternate molecular cause explaining the reported phenotype was identified, so BP5 could not be assessed. Details ▾Hide ▴
Rule
ACMG/AMP BP5
Evidence considered
- No alternate-cause data were present in the reviewed materials.
Still missing
- Case-level phenotype and alternate-cause evaluation were not available.
Sources
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, not a nonsense, frameshift, or canonical +/-1/2 splice variant, so the generic PVS1 loss-of-function framework does not apply even though MLH3 loss of function is considered a relevant disease mechanism at the gene level. Details ▾Hide ▴
Rule
generic ACMG PVS1 fallback
Evidence considered
- MLH3 was flagged as eligible for generic PVS1 consideration at the gene level.
- The variant-specific PVS1 assessment states that this variant does not fall into a default null-variant bucket.
Sources
PM4 N/AThis is a missense substitution and does not produce a protein length change or in-frame insertion/deletion. Details ▾Hide ▴
Rule
ACMG/AMP PM4
Evidence considered
- Protein consequence is p.(Arg637His).
PM5 N/APM5 was not applied because classic same-residue PM5 semantics could not be confirmed safely for this framework, and no qualifying pathogenic same-residue comparator variants were identified. Details ▾Hide ▴
Rule
ACMG/AMP PM5
Evidence considered
- PM5 candidate review found no eligible same-residue comparator variants and marked classic PM5 search as unsafe to apply automatically.
Still missing
- A validated same-residue pathogenic comparator would be needed if PM5 semantics were later confirmed.
Sources
pm5_candidates
PP5 N/AReputable-source assertions alone were not used because the available ClinVar submissions classify this variant as uncertain significance and do not provide independent evidence sufficient for PP5. Details ▾Hide ▴
Rule
ACMG/AMP PP5
Evidence considered
- ClinVar contains only uncertain-significance submissions without expert-panel review.
Sources
BP3 N/AThis is a single amino-acid substitution and not an in-frame insertion/deletion in a repetitive region without known function. Details ▾Hide ▴
Rule
ACMG/AMP BP3
Evidence considered
- Protein consequence is p.(Arg637His).
BP6 N/AReputable-source benign assertions alone were not used because the available ClinVar submissions classify this variant as uncertain significance, not likely benign or benign. Details ▾Hide ▴
Rule
ACMG/AMP BP6
Evidence considered
- ClinVar contains uncertain-significance submissions only.
Sources
BP7 N/ABP7 does not apply because this is not a synonymous or deep intronic variant. Details ▾Hide ▴
Rule
ACMG/AMP BP7
Evidence considered
- Protein consequence is p.(Arg637His).
Identifiers
- Gene
- MLH3
- Transcript
- NM_001040108.2
- Coding (HGVS c.)
- NM_001040108.2:c.1910G>A
- Protein (HGVS p.)
- NP_001035197.1:p.(Arg637His)
- GRCh38
- chr14:75047746 C>T
- GRCh37
- chr14:75514449 C>T
- ClinVar
- 1782502
- COSMIC
- COSV53152155
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
24 / 1,614,096 alleles
AF 1.49e-05 · 0 homozygotes · FAF 6.76e-05
gnomAD v2.1
12 / 282,480 alleles
AF 4.25e-05 · 0 homozygotes · FAF 0.000107
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.5e-05 · 24 / 1,614,096 alleles · 0 hom · FAF 6.8e-05
| Middle Eastern1 / 6,062 | 0.00016 |
| South Asian11 / 91,076 | 0.00012 |
| African/African American8 / 75,024 | 0.00011 |
| Remaining individuals2 / 62,506 | 3.2e-05 |
| East Asian1 / 44,882 | 2.2e-05 |
| Admixed American1 / 60,018 | 1.7e-05 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, Ashkenazi Jewish, European (non-Finnish).
gnomAD v2.1
AF 4.2e-05 · 12 / 282,480 alleles · 0 hom · FAF 0.00011
| South Asian7 / 30,600 | 0.00023 |
| African/African American3 / 24,964 | 0.00012 |
| East Asian2 / 19,948 | 0.0001 |
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.4869e-05; MAF= 0.00149%, 24/1614096 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164962; MAF= 0.01650%, 1/6062 alleles, homozygotes = 0); grpmax FAF= 6.763e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.24809e-05; MAF= 0.00425%, 12/282480 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000228758; MAF= 0.02288%, 7/30600 alleles, homozygotes = 0); grpmax FAF= 0.00010661.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.103
- BayesDel
- -0.486
How the predictions were used
BP4 SupportingMultiple computational findings support no deleterious effect. REVEL is low at 0.103, BayesDel is negative at -0.485573, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Rule
ACMG/AMP BP4
Evidence considered
- REVEL 0.103 supports a benign missense prediction.
- BayesDel -0.485573 supports a benign prediction.
- SpliceAI max delta 0.00 argues against splice disruption.
Sources
PP3 Available computational evidence does not support a damaging effect. REVEL is low at 0.103, BayesDel is negative at -0.485573, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00. Details ▾Hide ▴
Rule
ACMG/AMP PP3
Evidence considered
- REVEL 0.103.
- BayesDel -0.485573.
- SpliceAI max delta 0.00.
Sources
BP7 N/ABP7 does not apply because this is not a synonymous or deep intronic variant. Details ▾Hide ▴
Rule
ACMG/AMP BP7
Evidence considered
- Protein consequence is p.(Arg637His).
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.103. BayesDel score = -0.485573.
2 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
-
PMID 34043773 ↗European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third edition of the Mallorca guidelines based on gene and gender.Seppälä TT et al. · 2021No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
24 / 1,614,096 recorded alleles
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 ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1782502/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/14-75514449-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr14-75047746-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/14-75047746-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001040108.2%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/MLH3/R637H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=136504924
- 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
This variant is present in gnomAD v4.1 (AF= 1.4869e-05; MAF= 0.00149%, 24/1614096 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164962; MAF= 0.01650%, 1/6062 alleles, homozygotes = 0); grpmax FAF= 6.763e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.24809e-05; MAF= 0.00425%, 12/282480 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000228758; MAF= 0.02288%, 7/30600 alleles, homozygotes = 0); grpmax FAF= 0.00010661.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 1782502)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.103. BayesDel score = -0.485573.
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; COSV53152155, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.