About MLH3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MLH3 c.3488G>A, p.(Gly1163Asp)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
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
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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: 0
Benign evidence criteria: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BA1Stand alone
BA1 · stand alone
This variant exceeds the default BA1 population threshold of 1%. The highest observed population frequency is 2.83720% in East Asian individuals in gnomAD v2.1 and 2.24070% in East Asian individuals in gnomAD v4.1, both above 1%.
BS1Strong
BS1 · strong
This variant exceeds the default BS1 population threshold of 0.3%. The highest observed population frequency is 2.83720% in East Asian individuals in gnomAD v2.1 and 2.24070% in East Asian individuals in gnomAD v4.1, both well above 0.3%.
BP4Supporting
BP4 · supporting
Multiple computational results support a benign interpretation. SpliceAI shows no significant splice effect with a max delta score of 0.00, REVEL is low at 0.113, and BayesDel is negative at -0.258625, together arguing against a deleterious protein or splice effect.
Recorded classification: Benign
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong, BP4 supporting; combination = 1 stand-alone benign + 1 strong benign + 1 supporting benign, which maps to Benign.
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
1,147 / 1,591,542 alleles
gnomAD v4.1: 1,147 / 1,591,542 alleles. Recorded AF 0.000720685. Recorded homozygote count 9.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00212908; MAF= 0.21291%, 600/281812 alleles, homozygotes = 3) and has highest observed frequency in the East Asian population (AF= 0.028372; MAF= 2.83720%, 565/19914 alleles, homozygotes = 3); grpmax FAF= 0.0263843.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
Not assessed
No COSMIC evidence statement is recorded in this case.
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: 3 met · 11 not met · 12 not assessed · 2 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.3488G>A (p.Gly1163Asp; p.G1163D) variant has been reported in ClinVar, where most submissions classify it as benign (6 laboratories) and a minority classify it as uncertain significance (2 laboratories).
This variant is common in population databases, with East Asian allele frequencies of 2.83720% in gnomAD v2.1 and 2.24070% in gnomAD v4.1, exceeding the default BA1 threshold of 1% and BS1 threshold of 0.3%.
Computational evidence argues against a deleterious effect: SpliceAI predicts no significant splice impact with a max delta score of 0.00, REVEL is 0.113, and BayesDel is -0.258625.
No criteria match.
Met · 3
BA1 Stand aloneThis variant exceeds the default BA1 population threshold of 1%. The highest observed population frequency is 2.83720% in East Asian individuals in gnomAD v2.1 and 2.24070% in East Asian individuals in gnomAD v4.1, both above 1%. Details ▾Hide ▴
Rule
Generic ACMG population rule: BA1 if AF > 1%
Evidence considered
- gnomAD v2.1 East Asian AF 0.028372 (565/19914)
- 3 homozygotes.
- gnomAD v4.1 East Asian AF 0.022407 (989/44138)
- 7 homozygotes.
Sources
BS1 StrongThis variant exceeds the default BS1 population threshold of 0.3%. The highest observed population frequency is 2.83720% in East Asian individuals in gnomAD v2.1 and 2.24070% in East Asian individuals in gnomAD v4.1, both well above 0.3%. Details ▾Hide ▴
Rule
Generic ACMG population rule: BS1 if AF > 0.3%
Evidence considered
- gnomAD v2.1 East Asian AF 0.028372.
- gnomAD v4.1 East Asian AF 0.022407.
Sources
BP4 SupportingMultiple computational results support a benign interpretation. SpliceAI shows no significant splice effect with a max delta score of 0.00, REVEL is low at 0.113, and BayesDel is negative at -0.258625, together arguing against a deleterious protein or splice effect. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP4
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL score 0.113.
- BayesDel score -0.258625.
Sources
Not met · 11 · evaluated, threshold not reached
PVS1 This variant is a missense substitution, p.(Gly1163Asp), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Although gene-level review supports loss of function as a disease mechanism for MLH3, available evidence does not support applying PVS1 to this specific variant. Details ▾Hide ▴
Rule
Generic ACMG/AMP PVS1 with ClinGen SVI PVS1 fallback
Evidence considered
- MLH3 loss of function is considered eligible for generic PVS1 assessment at the gene level.
- The variant-level PVS1 scaffold states this change is outside the default null-variant buckets.
Still missing
- RNA or protein studies showing a null effect were not identified.
Sources
PS1 No evidence was identified that this exact amino acid change, p.(Gly1163Asp), is caused by a different nucleotide change already established as pathogenic. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PS1
Evidence considered
- ClinVar record reviewed for the exact variant.
Still missing
- A curated record of another pathogenic nucleotide change producing p.(Gly1163Asp) was not identified.
Sources
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PS2
Evidence considered
- ClinVar record reviewed
- no de novo evidence captured.
Still missing
- Parental testing data were not identified.
Sources
PS4 Available evidence does not show enrichment of this variant in affected individuals compared with controls. No case series or case-control data supporting increased prevalence in disease were identified. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PS4
Evidence considered
- ClinVar includes mixed benign and uncertain significance submissions.
- The variant is present at appreciable frequency in population databases.
Still missing
- Published affected-case counts or enrichment data for this exact variant were not identified.
Sources
PM1 This variant does not have evidence of occurring in a well-established mutational hotspot or a clearly defined critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this residue. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PM1
Evidence considered
- Cancer Hotspots review found no statistically significant hotspot row for G1163.
Still missing
- A narrowly defined critical residue cluster at codon 1163 was not identified.
Sources
PM2 This variant is not absent or rare in population databases. Its allele frequency is 0.21291% in gnomAD v2.1 and 0.07207% in gnomAD v4.1, both above the default PM2 threshold of 0.1%, and the highest East Asian frequencies are 2.83720% and 2.24070%, respectively. Details ▾Hide ▴
Rule
Generic ACMG population rule: PM2 if AF < 0.1%
Evidence considered
- gnomAD v2.1 total AF 0.00212908
- East Asian AF 0.028372.
- gnomAD v4.1 total AF 0.000720685
- East Asian AF 0.022407.
Sources
PM5 No evidence was identified that a different missense change at codon 1163 is already established as pathogenic. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PM5
Evidence considered
- ClinVar exact-variant review did not provide same-codon pathogenic missense evidence.
Still missing
- A pathogenic missense variant affecting the same codon was not identified.
Sources
PM6 No presumed de novo occurrence of this variant without confirmed parentage was identified. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PM6
Evidence considered
- ClinVar record reviewed
- no presumed de novo evidence captured.
Still missing
- Case-level parental testing information was not identified.
Sources
PP3 Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a max delta score of 0.00, REVEL is low at 0.113, and BayesDel is negative at -0.258625. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PP3
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL score 0.113.
- BayesDel score -0.258625.
Sources
PP5 A pathogenic assertion from a reputable source without accessible supporting evidence was not identified for this variant. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PP5
Evidence considered
- ClinVar shows benign and uncertain significance submissions
- not a pathogenic assertion.
Sources
BP6 A benign assertion from a reputable source without accessible supporting evidence was not used here because ClinVar submissions are mixed, with benign and uncertain significance classifications present rather than a single clear benign assertion. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP6
Evidence considered
- ClinVar reports 6 benign laboratory submissions and 2 uncertain significance submissions.
Sources
Not assessed · 12 · no assessment recorded
PS3 No well-established functional study of this exact variant was identified, so pathogenic functional evidence could not be assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PS3
Evidence considered
- Curated database review did not identify variant-specific reviewed functional evidence.
Still missing
- Variant-specific functional assay data were not identified.
Sources
PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease setting. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PM3
Evidence considered
- ClinVar record reviewed
- no trans observations captured.
Still missing
- Phase information and second-allele data were not identified.
Sources
PP1 No segregation data were identified for this variant, so co-segregation with disease could not be assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PP1
Evidence considered
- ClinVar review did not yield segregation information.
Still missing
- Pedigree or family testing data were not identified.
Sources
PP2 No gene-specific evidence was identified showing that pathogenic missense variation is a common mechanism in MLH3 and that benign missense variation is uncommon, so PP2 was not assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PP2
Evidence considered
- No MLH3-specific missense interpretation framework was available.
Still missing
- Gene-specific missense constraint or missense mechanism evidence was not identified.
Sources
PP4 No highly specific phenotype, family history, or tumor profile attributable to this exact variant was identified, so PP4 could not be assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PP4
Evidence considered
- Publicly available exact-variant record did not provide phenotype-specific case evidence sufficient for PP4.
Still missing
- Case-level phenotype and tumor data were not identified.
Sources
BS2 Although homozygotes are present in gnomAD, the disease-specific penetrance and inheritance context needed to apply BS2 were not established here, so BS2 was not assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BS2
Evidence considered
- gnomAD v2.1 reports 3 homozygotes.
- gnomAD v4.1 reports 9 homozygotes.
Still missing
- Gene- and condition-specific BS2 framework was not available.
Sources
BS3 No well-established functional study showing normal or near-normal function for this exact variant was identified, so benign functional evidence could not be assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BS3
Evidence considered
- Curated database review did not identify variant-specific reviewed functional evidence.
Still missing
- Variant-specific benign functional assay data were not identified.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 could not be assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BS4
Evidence considered
- No family non-segregation evidence identified in the exact-variant review.
Still missing
- Family studies showing lack of segregation were not identified.
Sources
BP1 This is a missense variant, but there was not enough gene-specific evidence to conclude that pathogenic variation in MLH3 is predominantly truncating with missense changes generally benign, so BP1 was not assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP1
Evidence considered
- Gene-level review supports loss of function as a mechanism
- but does not by itself establish BP1.
Still missing
- Gene-specific missense versus truncating pathogenicity spectrum was not established.
Sources
pvs1_gene_context
BP2 No data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant, so BP2 could not be assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP2
Evidence considered
- Exact-variant review did not provide phase data.
Still missing
- Phase information was not identified.
Sources
BP3 This criterion is intended for in-frame indels in repetitive regions, and no relevant evidence was identified for this missense variant. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP3
Evidence considered
- Variant consequence is missense
- not an in-frame indel.
Sources
BP5 No evidence was identified for an alternate molecular basis explaining the observed phenotype independent of this variant, so BP5 could not be assessed. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP5
Evidence considered
- No alternate molecular diagnosis data were identified in the exact-variant review.
Still missing
- Case-level alternate-cause data were not identified.
Sources
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PM4 N/AThis variant is a missense substitution and does not change protein length or involve an in-frame insertion or deletion, so PM4 is not applicable. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PM4
Evidence considered
- Variant consequence is p.(Gly1163Asp) missense.
Sources
BP7 N/ABP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP7
Evidence considered
- Variant consequence is p.(Gly1163Asp) missense.
Sources
Identifiers
- Gene
- MLH3
- Transcript
- NM_001040108.2
- Coding (HGVS c.)
- NM_001040108.2:c.3488G>A
- Protein (HGVS p.)
- NP_001035197.1:p.(Gly1163Asp)
- GRCh38
- chr14:75039993 C>T
- GRCh37
- chr14:75506696 C>T
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
1,147 / 1,591,542 alleles
AF 0.000721 · 9 homozygotes · FAF 0.0212
gnomAD v2.1
600 / 281,812 alleles
AF 0.00213 · 3 homozygotes · FAF 0.0264
By genetic ancestry
gnomAD v4.1
AF 0.00072 · 1147 / 1,591,542 alleles · 9 hom · FAF 0.021
| East Asian989 / 44,138 | 0.0227 hom |
| Remaining individuals84 / 61,558 | 0.00142 hom |
| African/African American38 / 74,270 | 0.00051 |
| Admixed American23 / 59,712 | 0.00039 |
| South Asian5 / 90,666 | 5.5e-05 |
| European (Finnish)1 / 62,856 | 1.6e-05 |
| European (non-Finnish)7 / 1,162,110 | 6e-06 |
0 alternate alleles recorded in 3 other groups: Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 0.0021 · 600 / 281,812 alleles · 3 hom · FAF 0.026
| East Asian565 / 19,914 | 0.0283 hom |
| Remaining individuals7 / 7,180 | 0.00097 |
| African/African American19 / 24,850 | 0.00076 |
| Admixed American6 / 35,376 | 0.00017 |
| South Asian2 / 30,612 | 6.5e-05 |
| European (non-Finnish)1 / 128,946 | 7.8e-06 |
0 alternate alleles recorded in 2 other groups: Ashkenazi Jewish, European (Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000720685; MAF= 0.07207%, 1147/1591542 alleles, homozygotes = 9) and has highest observed frequency in the East Asian population (AF= 0.022407; MAF= 2.24070%, 989/44138 alleles, homozygotes = 7); grpmax FAF= 0.0212477.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00212908; MAF= 0.21291%, 600/281812 alleles, homozygotes = 3) and has highest observed frequency in the East Asian population (AF= 0.028372; MAF= 2.83720%, 565/19914 alleles, homozygotes = 3); grpmax FAF= 0.0263843.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingMultiple computational results support a benign interpretation. SpliceAI shows no significant splice effect with a max delta score of 0.00, REVEL is low at 0.113, and BayesDel is negative at -0.258625, together arguing against a deleterious protein or splice effect. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP4
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL score 0.113.
- BayesDel score -0.258625.
Sources
PP3 Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a max delta score of 0.00, REVEL is low at 0.113, and BayesDel is negative at -0.258625. Details ▾Hide ▴
Rule
ACMG/AMP 2015 PP3
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL score 0.113.
- BayesDel score -0.258625.
Sources
BP7 N/ABP7 applies to synonymous or certain intronic variants with no predicted splice impact. This variant is missense, so BP7 is not applicable. Details ▾Hide ▴
Rule
ACMG/AMP 2015 BP7
Evidence considered
- Variant consequence is p.(Gly1163Asp) missense.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.113. BayesDel score = -0.258625.
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
1,147 / 1,591,542 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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/416458/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/14-75506696-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr14-75039993-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001040108.2%3Ac.3…
- OncoKB ↗www.oncokb.org/gene/MLH3/G1163D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=114806507
- 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= 0.000720685; MAF= 0.07207%, 1147/1591542 alleles, homozygotes = 9) and has highest observed frequency in the East Asian population (AF= 0.022407; MAF= 2.24070%, 989/44138 alleles, homozygotes = 7); grpmax FAF= 0.0212477.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00212908; MAF= 0.21291%, 600/281812 alleles, homozygotes = 3) and has highest observed frequency in the East Asian population (AF= 0.028372; MAF= 2.83720%, 565/19914 alleles, homozygotes = 3); grpmax FAF= 0.0263843.
ClinVar
This variant has been reported in ClinVar as Benign (6 clinical laboratories) and as Uncertain significance (2 clinical laboratories).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.113. BayesDel score = -0.258625.
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; COSV105867929, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.