About MLH3
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MLH3 c.3637G>A, p.(Glu1213Lys)
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: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.068 (strongly benign-leaning), BayesDel score -0.421 (benign-leaning), and SpliceAI max delta score 0.04 (no predicted splicing impact). All three concordant in silico predictors support a benign interpretation.
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: BP4 supporting benign; combination = 1 supporting benign, 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
232 / 1,612,714 alleles
gnomAD v4.1: 232 / 1,612,714 alleles. Recorded AF 0.000143857. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000113135; MAF= 0.01131%, 32/282848 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000276778; MAF= 0.02768%, 2/7226 alleles, homozygotes = 0); grpmax FAF= 0.00013731.
No listed criterion applied
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
5 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
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 16 not met · 7 not assessed · 5 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.3637G>A (p.Glu1213Lys) is a missense variant in exon 6 of MLH3, a mismatch repair gene associated with Lynch syndrome and polyposis predisposition.
This variant is present in gnomAD population databases at low frequency: v2.1 AF=0.0113% (32/282,848 alleles) and v4.1 AF=0.0144% (232/1,612,714 alleles), with no homozygotes observed. It does not meet BA1 (>1%), BS1 (>0.3%), or PM2 (absent/extremely low) population frequency thresholds.
ClinVar reports this variant as Uncertain Significance based on submissions from 5 clinical laboratories (ClinVar variation ID 847280). No expert panel review or pathogenic classification is available.
Multiple in silico predictors concordantly suggest a benign effect: REVEL score 0.068, BayesDel score -0.421, and SpliceAI max delta 0.04, supporting BP4 (supporting benign).
No variant-specific functional studies, segregation data, de novo occurrences, case-control enrichment, or pathogenic comparator variants at the same residue were identified. No publications specifically mention this variant.
The only met criterion is BP4 (supporting benign). No pathogenic or other benign criteria are met. The evidence is insufficient to classify this variant beyond Uncertain Significance under generic ACMG/AMP 2015 rules.
No criteria match.
Met · 1
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.068 (strongly benign-leaning), BayesDel score -0.421 (benign-leaning), and SpliceAI max delta score 0.04 (no predicted splicing impact). All three concordant in silico predictors support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.068 (benign-leaning
- threshold for pathogenic typically >0.5). BayesDel: -0.421 (negative score indicates benign). SpliceAI max delta: 0.04 (no splicing alteration predicted
- threshold for effect typically ≥0.2).
Sources
Not met · 16 · evaluated, threshold not reached
PS2 No de novo occurrence of NM_001040108.2:c.3637G>A has been reported in the literature or population databases. PS2 requires confirmation of de novo status with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo reports found in ClinVar
- literature
- or exploratory evidence recovery.
Still missing
- No de novo observation reported for this variant.
PS3 No variant-specific functional studies (in vitro or in vivo) demonstrating a deleterious effect were identified for MLH3 p.Glu1213Lys. OncoKB reports unknown oncogenic effect with no variant-specific functional evidence curated. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional data curated. Wu et al. 2005 (PMID:16216036) assayed MLH3 missense variants but did not include E1213K.
Still missing
- No dedicated functional assay assessing mismatch repair activity
- protein stability
- or interaction for p.Glu1213Lys.
Sources
PS4 The variant is present in gnomAD population databases at low frequency (v2.1: 0.0113%; v4.1: 0.0144%) with no evidence of statistically significant enrichment in affected individuals over controls. No case-control studies report this variant. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 32/282
- 848 alleles (AF=0.0113%)
- gnomAD v4.1: 232/1
- 612
- 714 alleles (AF=0.0144%). No case-control enrichment data available.
Still missing
- No case-control study specifically comparing MLH3 c.3637G>A frequency in affected vs. unaffected individuals.
Sources
PM1 Residue Glu1213 lies in the C-terminal region of MLH3 outside well-defined functional domains. The variant does not lie in a statistically significant mutational hotspot (hotspots screen negative). No critical functional domain identified at this position. Details ▾Hide ▴
Evidence considered
- Hotspot screen: residue not significant
- exact variant not listed. Exploratory evidence: no clustering of pathogenic mutations at codon 1213.
Still missing
- No structural or functional data indicating critical relevance of residue E1213.
PM2 The variant is present in gnomAD population databases (v2.1: 32/282,848 alleles, AF=0.0113%; v4.1: 232/1,612,714 alleles, AF=0.0144%). It is not absent from population controls; PM2 requires absence or extremely low frequency in population databases. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.0113% (32 alleles)
- gnomAD v4.1 AF=0.0144% (232 alleles). Variant is present
- not absent.
Sources
PM5 No pathogenic missense variant at the same amino acid residue (Glu1213) has been identified. Automated PM5 candidate harvesting returned no candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: found=false
- no same-residue pathogenic comparators identified in ClinVar.
Still missing
- No established pathogenic missense variant at Glu1213 for PM5 comparison.
Sources
pm5_candidates
PM6 No de novo occurrence of this variant has been reported in the literature or databases. PM6 requires confirmed de novo status without confirmation of paternity and maternity. Details ▾Hide ▴
Evidence considered
- Exploratory evidence recovery: no de novo observations identified.
Still missing
- No de novo reports for this variant.
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score 0.068 (benign-leaning), BayesDel score -0.421 (benign-leaning), and SpliceAI max delta 0.04 (no predicted splicing impact). PP3 requires computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.068 (range 0-1
- higher = pathogenic
- 0.068 is strongly benign-leaning). BayesDel: -0.421 (negative score = benign-leaning). SpliceAI max delta: 0.04 (no significant splice impact).
Sources
PP5 ClinVar classification for this variant is Uncertain Significance (5 clinical laboratories, criteria provided, single submitter). No reputable source has classified this variant as pathogenic. PP5 requires a reputable source to report the variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: variation ID 847280
- classification Uncertain Significance
- review status 'criteria provided
- single submitter'.
Sources
BA1 gnomAD v2.1 allele frequency is 0.0113% (32/282,848 alleles) and v4.1 allele frequency is 0.0144% (232/1,612,714 alleles). Neither exceeds the BA1 threshold of >1% for a standing-alone benign criterion. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.0113% (below 1% BA1 cutoff)
- gnomAD v4.1 AF=0.0144% (below 1% BA1 cutoff).
Sources
BS1 gnomAD v2.1 allele frequency is 0.0113% and v4.1 allele frequency is 0.0144%. Neither exceeds the BS1 threshold of >0.3% for a strong benign population frequency criterion. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.0113% (below 0.3% BS1 cutoff)
- gnomAD v4.1 AF=0.0144% (below 0.3% BS1 cutoff).
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on MLH3 protein function or splicing were identified for this variant. BS3 requires direct functional evidence of a benign effect. Details ▾Hide ▴
Evidence considered
- OncoKB reports unknown oncogenic effect with no variant-specific functional studies. In silico predictions (REVEL
- BayesDel) are benign-leaning but are not functional assays.
Still missing
- No dedicated functional assay assessing mismatch repair activity
- protein stability
- or interaction for p.Glu1213Lys.
Sources
BP1 While biallelic MLH3 loss-of-function (truncating) variants are associated with polyposis predisposition (PMID:30573798), MLH3 is not established as a gene where primarily truncating variants cause disease to the exclusion of missense variants. Missense variants have been reported in association with MLH3-related phenotypes. Details ▾Hide ▴
Evidence considered
- PVS1 gene context confirms MLH3 LoF mechanism supported
- however
- both truncating and missense variants are reported. MLH3 is not established as a 'primarily truncating' disease gene.
Still missing
- No systematic assessment of MLH3 missense vs. truncating variant pathogenicity spectrum.
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a known pathogenic MLH3 variant in a healthy individual has been reported. gnomAD shows zero homozygotes for this variant. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 and v4.1: zero homozygotes. No reports of this variant in trans with a pathogenic MLH3 variant.
Still missing
- No cis/trans phase data available for this variant relative to other MLH3 variants.
Sources
BP5 No case has been identified in which this variant is found alongside an alternate molecular basis for disease. BP5 requires a variant to be found in a case with an established alternate molecular cause. Details ▾Hide ▴
Evidence considered
- No reports of alternate molecular diagnoses in individuals carrying this variant.
Still missing
- No cases with alternate molecular basis identified.
BP6 No reputable source has classified this variant as benign. ClinVar classification is Uncertain Significance (5 clinical laboratories). BP6 requires a reputable source to report the variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar variation 847280: classification is Uncertain Significance
- not benign.
Sources
Not assessed · 7 · no assessment recorded
PS1 No established pathogenic variant at amino acid residue E1213 with the same amino acid change (Glu1213Lys) was identified in ClinVar or the literature to satisfy PS1 criteria. Details ▾Hide ▴
Evidence considered
- ClinVar variation 847280 lists this variant as VUS
- no other pathogenic missense at E1213 identified.
Still missing
- No known pathogenic variant at the same residue with the same amino acid change.
Sources
PP1 No published co-segregation studies involving NM_001040108.2:c.3637G>A in families with MLH3-associated disease were identified. PP1 requires demonstration of co-segregation with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No segregation data found in literature or ClinVar submissions.
Still missing
- No family segregation studies available for this variant.
PP2 Insufficient evidence to determine whether MLH3 has a low rate of benign missense variation and whether missense variants are a common mechanism of disease. MLH3 is not a well-characterized gene for PP2 application in generic ACMG framework. Details ▾Hide ▴
Evidence considered
- MLH3 disease mechanism involves both truncating and missense variants
- gene not established as meeting PP2 prerequisites.
Still missing
- No gene-level missense constraint metrics or established missense disease mechanism for MLH3.
PP4 No specific patient phenotype or family history data were available for assessment. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No phenotypic data provided for the proband or family.
Still missing
- Patient phenotype and family history data not provided for review.
BS2 The variant is observed in heterozygous state in gnomAD (32 alleles in v2.1, 232 alleles in v4.1, zero homozygotes), but individual-level clinical confirmation of healthy adult status is not available. MLH3-associated disease may exhibit recessive inheritance with incomplete penetrance, complicating direct BS2 application without clinical context. Details ▾Hide ▴
Evidence considered
- gnomAD shows heterozygous carriers in presumably healthy population
- zero homozygotes. No individual clinical data confirming healthy phenotype available.
Still missing
- Lack of individual-level phenotype data for gnomAD carriers
- uncertain disease inheritance pattern and penetrance for MLH3.
Sources
BS4 No family segregation data are available for this variant. BS4 requires lack of segregation in affected members of a family; this cannot be assessed without family genotype and phenotype data. Details ▾Hide ▴
Evidence considered
- No segregation or non-segregation data identified in ClinVar or the literature.
Still missing
- No family studies with genotype-phenotype correlation for this variant.
PS5 No different pathogenic variant at the same nucleotide position (c.3637) has been established. PS5 requires a different pathogenic nucleotide change at the same position. Details ▾Hide ▴
Evidence considered
- No alternative pathogenic variant at c.3637 identified in ClinVar or the literature.
Still missing
- No established pathogenic variant at nucleotide position c.3637 for comparison.
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Glu1213Lys); does not fall into null-variant buckets (nonsense, frameshift, canonical ±1,2 splice consensus) per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution at c.3637
- variant bucket 'other'
- generic PVS1 framework not triggered.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ASkipped per case instructions; no biallelic observation data assessed. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AVariant is a missense substitution, not an in-frame deletion or insertion. PM4 applies only to protein-length-altering variants. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (c.3637G>A, p.Glu1213Lys), not a synonymous (silent) variant. BP7 applies exclusively to synonymous variants. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- MLH3
- Transcript
- NM_001040108.2
- Coding (HGVS c.)
- NM_001040108.2:c.3637G>A
- Protein (HGVS p.)
- NP_001035197.1:p.(Glu1213Lys)
- GRCh38
- chr14:75038346 C>T
- GRCh37
- chr14:75505049 C>T
- ClinVar
- 847280
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
232 / 1,612,714 alleles
AF 0.000144 · 0 homozygotes · FAF 0.000151
gnomAD v2.1
32 / 282,848 alleles
AF 0.000113 · 0 homozygotes · FAF 0.000137
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 0.00014 · 232 / 1,612,714 alleles · 0 hom · FAF 0.00015
| European (Finnish)20 / 63,958 | 0.00031 |
| European (non-Finnish)201 / 1,178,786 | 0.00017 |
| Remaining individuals4 / 62,460 | 6.4e-05 |
| African/African American4 / 75,002 | 5.3e-05 |
| Ashkenazi Jewish1 / 29,592 | 3.4e-05 |
| Admixed American1 / 60,022 | 1.7e-05 |
| South Asian1 / 91,044 | 1.1e-05 |
0 alternate alleles recorded in 3 other groups: Amish, East Asian, Middle Eastern.
gnomAD v2.1
AF 0.00011 · 32 / 282,848 alleles · 0 hom · FAF 0.00014
| Remaining individuals2 / 7,226 | 0.00028 |
| European (Finnish)5 / 25,088 | 0.0002 |
| European (non-Finnish)24 / 129,196 | 0.00019 |
| African/African American1 / 24,964 | 4e-05 |
0 alternate alleles recorded in 4 other groups: Admixed American, Ashkenazi Jewish, East Asian, South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000143857; MAF= 0.01439%, 232/1612714 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000312705; MAF= 0.03127%, 20/63958 alleles, homozygotes = 0); grpmax FAF= 0.00015121.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000113135; MAF= 0.01131%, 32/282848 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000276778; MAF= 0.02768%, 2/7226 alleles, homozygotes = 0); grpmax FAF= 0.00013731.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.068
- BayesDel
- -0.421
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: REVEL score 0.068 (strongly benign-leaning), BayesDel score -0.421 (benign-leaning), and SpliceAI max delta score 0.04 (no predicted splicing impact). All three concordant in silico predictors support a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.068 (benign-leaning
- threshold for pathogenic typically >0.5). BayesDel: -0.421 (negative score indicates benign). SpliceAI max delta: 0.04 (no splicing alteration predicted
- threshold for effect typically ≥0.2).
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score 0.068 (benign-leaning), BayesDel score -0.421 (benign-leaning), and SpliceAI max delta 0.04 (no predicted splicing impact). PP3 requires computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.068 (range 0-1
- higher = pathogenic
- 0.068 is strongly benign-leaning). BayesDel: -0.421 (negative score = benign-leaning). SpliceAI max delta: 0.04 (no significant splice impact).
Sources
BP7 N/AThis is a missense variant (c.3637G>A, p.Glu1213Lys), not a synonymous (silent) variant. BP7 applies exclusively to synonymous variants. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.068. BayesDel score = -0.421174.
11 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
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015No paper-specific finding is recorded.
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PMID 20301390 ↗Lynch Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 24493721 ↗American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.Lu KH et al. · 2014No paper-specific finding is recorded.
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
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PMID 26389505 ↗Genetics of Colorectal Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
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PMID 33451724 ↗Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations, part II.Hamilton CA et al. · 2021No paper-specific finding is recorded.
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PMID 33516529 ↗Endometrial cancer: A society of gynecologic oncology evidence-based review and recommendations.Hamilton CA et al. · 2021No paper-specific finding is recorded.
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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.
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PMID 24905773 ↗Endometrial cancer: a review and current management strategies: part I.SGO Clinical Practice Endometrial Cancer Working Group et al. · 2014No paper-specific finding is recorded.
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PMID 24929052 ↗Endometrial cancer: a review and current management strategies: part II.SGO Clinical Practice Endometrial Cancer Working Group et al. · 2014No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
232 / 1,612,714 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
5 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/847280/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/14-75505049-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr14-75038346-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001040108.2%3Ac.3…
- OncoKB ↗www.oncokb.org/gene/MLH3/E1213K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MLH3+c.3637G%3EA
- 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= 0.000143857; MAF= 0.01439%, 232/1612714 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000312705; MAF= 0.03127%, 20/63958 alleles, homozygotes = 0); grpmax FAF= 0.00015121.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000113135; MAF= 0.01131%, 32/282848 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000276778; MAF= 0.02768%, 2/7226 alleles, homozygotes = 0); grpmax FAF= 0.00013731.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 847280)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.068. BayesDel score = -0.421174.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.