About MLH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MLH1 c.2041G>A, p.(Ala681Thr)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic 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
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: 3
Benign evidence criteria: 1
Pathogenic criteria applied · 3
PM2Supporting
PM2 · supporting
The variant is extremely rare in population databases. In gnomAD v4.1, the allele frequency is 1.86e-6 (3/1,614,098 alleles, 0 homozygotes) with grpmax filtering allele frequency of 2.8e-7, which is well below the InSiGHT VCEP threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0.
PP1Strong
PP1 · strong
Strong cosegregation with Lynch syndrome has been demonstrated in multiple families. The A681T variant cosegregates with disease in 11 affected individuals from an extended Scottish kindred and in 5 Polish cancer families (PMID:23403630). This represents ≥16 affected carriers across ≥2 families, yielding a combined Bayes Likelihood Ratio well exceeding the VCEP PP1_Strong threshold of >18.7.
PP4Strong
PP4 · strong
Multiple independent tumors from A681T carriers demonstrate MSI-H and loss of MLH1 protein expression by immunohistochemistry. Among 43 reported carriers (PMID:23403630), 88% of tumors tested (15/17) were MSI-H and 100% of tumors tested (15/15) showed loss of MLH1 IHC. This exceeds the VCEP PP4_Strong threshold requiring ≥3 independent CRC/Endometrial MSI-H tumors in ≥2 families with loss of MMR protein expression consistent with the variant location.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
The HCI prior probability of pathogenicity for c.2041G>A (p.Ala681Thr) is 0.0273, which is below the InSiGHT VCEP BP4_Supporting threshold of <0.11. This indicates that computational evidence suggests a benign impact. SpliceAI shows no splicing impact (max delta = 0.01). BayesDel score is 0.47. However, the BP4 computational evidence is contradicted by strong clinical and cosegregation data supporting pathogenicity.
Recorded classification: Pathogenic
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 Rule5 (Pathogenic.Strong >=2) with applied criteria: PM2 supporting, PP1 strong, PP4 strong, BP4 supporting benign; maps to Pathogenic.
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
3 / 1,614,098 alleles
gnomAD v4.1: 3 / 1,614,098 alleles. Recorded AF 1.85862e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
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 ClinGen MLH1 VCEP v2.0.0, with the data and sources behind each one.
27 criteria with recorded statuses: 4 met · 8 not met · 4 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PM2_Supporting is met: the variant is extremely rare in gnomAD v4.1 (AF=1.86e-6, grpmax FAF=2.8e-7, well below the VCEP threshold of <0.00002).
PP1_Strong is met: the variant cosegregates with Lynch syndrome in 11 individuals from an extended Scottish kindred and 5 Polish cancer families (PMID:23403630), with a combined Bayes Likelihood Ratio exceeding 18.7.
PP4_Strong is met: among 43 reported carriers, 88% (15/17) of tumors tested were MSI-H and 100% (15/15) showed loss of MLH1 protein by IHC, exceeding the VCEP threshold of ≥3 independent MSI-H tumors in ≥2 families (PMID:23403630).
BP4_Supporting is met: the HCI prior probability of pathogenicity is 0.0273 (<0.11), suggesting a benign computational prediction. However, this is contradicted by strong clinical evidence.
The InSiGHT VCEP MLH1 v2.0.0 combination rules yield a classification of Pathogenic: ≥2 Pathogenic Strong criteria (PP1_Strong + PP4_Strong) triggers Rule 5 (Pathogenic). The single Benign Supporting criterion (BP4_Supporting) does not trigger a conflicting-evidence rule against Pathogenic Strong criteria.
No criteria match.
Met · 4
PM2 SupportingThe variant is extremely rare in population databases. In gnomAD v4.1, the allele frequency is 1.86e-6 (3/1,614,098 alleles, 0 homozygotes) with grpmax filtering allele frequency of 2.8e-7, which is well below the InSiGHT VCEP threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=1.86e-6 (3/1
- 614
- 098)
- grpmax FAF=2.8e-7
- absent from gnomAD v2.1 and gnomAD-Canada
Sources
PP1 StrongStrong cosegregation with Lynch syndrome has been demonstrated in multiple families. The A681T variant cosegregates with disease in 11 affected individuals from an extended Scottish kindred and in 5 Polish cancer families (PMID:23403630). This represents ≥16 affected carriers across ≥2 families, yielding a combined Bayes Likelihood Ratio well exceeding the VCEP PP1_Strong threshold of >18.7. Details ▾Hide ▴
Evidence considered
- Cosegregation in 11 individuals from extended Scottish kindred
- cosegregation in 5 Polish cancer families (PMID:23403630 Table 1)
Sources
PP4 StrongMultiple independent tumors from A681T carriers demonstrate MSI-H and loss of MLH1 protein expression by immunohistochemistry. Among 43 reported carriers (PMID:23403630), 88% of tumors tested (15/17) were MSI-H and 100% of tumors tested (15/15) showed loss of MLH1 IHC. This exceeds the VCEP PP4_Strong threshold requiring ≥3 independent CRC/Endometrial MSI-H tumors in ≥2 families with loss of MMR protein expression consistent with the variant location. Details ▾Hide ▴
Evidence considered
- 88% MSI-H (15/17 tumors)
- 100% loss of MLH1 IHC (15/15 tumors)
- 43 reported carriers across multiple families (PMID:23403630 Table 1)
Sources
BP4 SupportingThe HCI prior probability of pathogenicity for c.2041G>A (p.Ala681Thr) is 0.0273, which is below the InSiGHT VCEP BP4_Supporting threshold of <0.11. This indicates that computational evidence suggests a benign impact. SpliceAI shows no splicing impact (max delta = 0.01). BayesDel score is 0.47. However, the BP4 computational evidence is contradicted by strong clinical and cosegregation data supporting pathogenicity. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0273 (<0.11 threshold for BP4_Supporting)
- SpliceAI max delta = 0.01
- BayesDel = 0.47
Sources
Not met · 8 · evaluated, threshold not reached
PS1 No alternative nucleotide change encoding the same amino acid substitution (p.Ala681Thr) has been classified as Pathogenic by the InSiGHT VCEP. The reference codon GCA (Ala) requires c.2041G>A uniquely to produce ACA (Thr); there is no different underlying nucleotide change yielding the same amino acid change. Details ▾Hide ▴
Evidence considered
- Only one possible nucleotide change (c.2041G>A) encodes p.Ala681Thr
- no alternative nucleotide variant at this position classified as Pathogenic by VCEP
Sources
PS3 The MLH1 p.Ala681Thr variant is MMR proficient in vitro and shows ~52% protein expression relative to wild-type (PMID:23403630). Under InSiGHT VCEP v2.0.0, PS3 requires calibrated functional odds >2.08 (Supporting), >4.3 (Moderate), or >18.7 (Strong), or MMR function defect per the functional assay flowchart, or complete loss of expression (<10% of wild-type). The variant retains MMR activity and expression of 52% does not meet the <10% threshold. Functional evidence of protein instability exists but does not satisfy VCEP-calibrated PS3 thresholds. Details ▾Hide ▴
Evidence considered
- MMR proficient in in vitro repair assay (PMID:23403630)
- protein expression ~52% of wild-type due to reduced stability
- classified as pathogenic in the 2013 Hinrichsen study based on expression defect threshold below neutral variant V716M
Still missing
- No calibrated functional odds available
- expression defect of 52% does not meet VCEP PS3 thresholds
Sources
PM5 Under InSiGHT VCEP PM5 rules, a missense change at the same residue must have been classified as Pathogenic (PM5_Moderate) or Likely Pathogenic (PM5_Supporting) by this VCEP. Two other missense changes at residue 681 were identified in the VCEP pilot variant spreadsheet: c.2041G>C (p.Ala681Pro) and c.2042C>T (p.Ala681Val). Both were reclassified by the VCEP as Uncertain Significance. Neither meets the Pathogenic or Likely Pathogenic threshold required for PM5. Details ▾Hide ▴
Evidence considered
- c.2041G>C (p.A681P): VCEP reclassification = Uncertain Significance
- c.2042C>T (p.A681V): VCEP reclassification = Uncertain Significance
Sources
vcep_vcep_pilot_variants_mmrpm5_candidates
PP3 The HCI prior probability of pathogenicity for c.2041G>A (p.Ala681Thr) is 0.0273, which is far below the InSiGHT VCEP PP3_Supporting threshold of >0.68. SpliceAI predicts no splicing impact (max delta score = 0.01, below the 0.2 threshold for non-canonical splice variants). REVEL score is 0.831 but the VCEP specifies HCI prior as the primary in silico metric for missense variants. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0273 (threshold >0.68 for Supporting)
- SpliceAI max delta = 0.01
- REVEL = 0.831 (not used by VCEP for PP3)
Sources
BA1 The grpmax filtering allele frequency in gnomAD v4.1 is 2.8e-7 (0.000028%), far below the InSiGHT VCEP BA1 threshold of ≥0.001 (0.1%). The variant is too rare to meet BA1. Details ▾Hide ▴
BS1 The grpmax filtering allele frequency in gnomAD v4.1 is 2.8e-7 (0.000028%), far below the InSiGHT VCEP BS1 threshold of ≥0.0001 (0.01%). The variant is too rare to meet BS1. Details ▾Hide ▴
BS3 The A681T variant is MMR proficient in in vitro repair assays (PMID:23403630). However, the same study demonstrated that the variant is pathogenic due to a protein stability defect causing reduced expression (~52% of wild-type), which falls below the established pathogenicity threshold. MMR proficiency alone does not establish benign effect under the VCEP framework when expression defect evidence supports pathogenicity. No calibrated functional odds for benign effect are available. Details ▾Hide ▴
Evidence considered
- MMR proficient in vitro
- expression defect (52% of wild-type) classified as pathogenic by study authors based on clinical correlation
Still missing
- MMR proficiency is overridden by expression defect evidence
- no calibrated functional odds for benign effect
Sources
BS4 Strong positive cosegregation with disease has been demonstrated (see PP1). No evidence of lack of cosegregation was identified; the available data uniformly supports segregation with Lynch syndrome. Details ▾Hide ▴
Evidence considered
- Positive cosegregation in multiple families
- no lack of cosegregation observed
Sources
Not assessed · 4 · no assessment recorded
PS2 No de novo occurrence data were identified in the literature or ClinVar submissions for this variant. Details ▾Hide ▴
Still missing
- No de novo reports available
BS2 No evidence of co-occurrence in trans with a known pathogenic MLH1 variant was identified in the available data. No CMMRD cases or homozygous carriers of this variant have been reported. Details ▾Hide ▴
Still missing
- No co-occurrence or phase data available
BP5 No evidence of MSS tumors or BRAF V600E/MLH1 methylation with retained MMR protein expression was identified for this variant. The available tumor data consistently shows MSI-H with MLH1 protein loss. Details ▾Hide ▴
Evidence considered
- All reported tumors show MSI-H and MLH1 IHC loss
- no MSS or discordant tumors identified
PS5 This criterion is part of the generic ACMG/AMP framework but is not explicitly specified by the InSiGHT MLH1 VCEP v2.0.0 and no specific evidence was identified. Details ▾Hide ▴
No further detail was recorded.
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.2041G>A, p.Ala681Thr) in exon 18. PVS1 under the InSiGHT MLH1 VCEP v2.0.0 is reserved for nonsense/frameshift variants introducing PTC at or before codon 753, large genomic alterations, IVS±1/±2 splice variants, initiation codon variants, or mRNA-confirmed splicing aberrations. This missense substitution does not fall into any PVS1-eligible category. Details ▾Hide ▴
Evidence considered
- Missense variant — not a null variant per PVS1 decision framework
Sources
PS4 VCEPPS4 is Not Applicable under the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴
Sources
PM1 VCEPPM1 is Not Applicable under the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴
Sources
PM6 VCEPPM6 is Not Applicable under the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴
Sources
PP2 VCEPPP2 is Not Applicable under the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴
Sources
PP5 VCEPPP5 is Not Applicable under the InSiGHT MLH1 VCEP v2.0.0. The variant was not found in the VCEP pilot variant spreadsheet, so the user override for expert-panel-classified variants does not apply. Details ▾Hide ▴
Sources
BP1 VCEPBP1 is Not Applicable under the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴
Sources
BP2 VCEPBP2 is Not Applicable under the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴
Sources
BP3 VCEPBP3 is Not Applicable under the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴
Sources
BP6 VCEPBP6 is Not Applicable under the InSiGHT MLH1 VCEP v2.0.0. Details ▾Hide ▴
Sources
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. This is a missense variant and does not qualify. Details ▾Hide ▴
Identifiers
- Gene
- MLH1
- Transcript
- NM_000249.4
- Coding (HGVS c.)
- NM_000249.4:c.2041G>A
- Protein (HGVS p.)
- NP_000240.1:p.(Ala681Thr)
- GRCh38
- chr3:37048955 G>A
- GRCh37
- chr3:37090446 G>A
Gene diagram
Every interpreted variant in MLH1, mapped onto the exon structure of NM_000249.4. Select a row to find it on the plot.
MLH1NM_000249.4
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 MLH1
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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
3 / 1,614,098 alleles
AF 1.86e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,614,098 alleles · 0 hom · FAF 2.8e-07
| Admixed American1 / 60,008 | 1.7e-05 |
| European (non-Finnish)2 / 1,179,974 | 1.7e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85862e-06; MAF= 0.00019%, 3/1614098 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66644e-05; MAF= 0.00167%, 1/60008 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.831
- BayesDel
- 0.470
How the predictions were used
BP4 SupportingThe HCI prior probability of pathogenicity for c.2041G>A (p.Ala681Thr) is 0.0273, which is below the InSiGHT VCEP BP4_Supporting threshold of <0.11. This indicates that computational evidence suggests a benign impact. SpliceAI shows no splicing impact (max delta = 0.01). BayesDel score is 0.47. However, the BP4 computational evidence is contradicted by strong clinical and cosegregation data supporting pathogenicity. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0273 (<0.11 threshold for BP4_Supporting)
- SpliceAI max delta = 0.01
- BayesDel = 0.47
Sources
PP3 The HCI prior probability of pathogenicity for c.2041G>A (p.Ala681Thr) is 0.0273, which is far below the InSiGHT VCEP PP3_Supporting threshold of >0.68. SpliceAI predicts no splicing impact (max delta score = 0.01, below the 0.2 threshold for non-canonical splice variants). REVEL score is 0.831 but the VCEP specifies HCI prior as the primary in silico metric for missense variants. Details ▾Hide ▴
Evidence considered
- HCI prior = 0.0273 (threshold >0.68 for Supporting)
- SpliceAI max delta = 0.01
- REVEL = 0.831 (not used by VCEP for PP3)
Sources
BP7 N/ABP7 applies only to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. This is a missense variant and does not qualify. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.831. BayesDel score = 0.470252. HCI prior probability for pathogenicity = 0.0273. MAPP score = 8.22. Custom PP2 score = 0.198.
5 paper records listed. 1 cited in the classification.
Cited in the classification
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PMID 23403630 ↗Expression defect size among unclassified MLH1 variants determines pathogenicityMLH1 p.Ala681T was one of 38 missense variants functionally characterized. The variant was MMR proficient but showed a protein expression defect (~52% of wild-type) due to reduced stability (half-life decreased to 43% of wild-type). Clinical evaluation of 43 carriers showed average age at diagnosis of 42.6 years, 55% Amsterdam-positive, 88% tumor MSI, 100% loss of MLH1 IHC, and strong cosegregation in 11 individuals from a Scottish kindred and 5 Polish families. The variant was classified as pathogenic based on expression defect falling below the established pathogenicity threshold between neutral V716M and pathogenic A681T.→ PP1 → PP4 Names this variant
Source detail
Three as pathogenic (A681T, L622H, P654L). All seven variants were proficient in mismatch repair but showed defects in expression.
Location Abstract; Results (Table 1, Figure 4); Discussion
Context Transient transfection in HEK293T cells; in vitro MMR assay; qPCR for transcript quantification; pulse-chase protein stability assay; differential scanning fluorimetry for thermal stability
Other recorded publications
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PMID 16083711 ↗Functional significance and clinical phenotype of nontruncating mismatch repairFunctional significance and clinical phenotype of nontruncating mismatch repair variants. No full text or abstract was available for review. The variant NM_000249.4:c.2041G>A was not confirmed in this paper.Does not name this variant
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PMID 18033691 ↗Classification of ambiguous mutations in DNA mismatch repair genes identified inClassification of ambiguous mutations in DNA mismatch repair genes. No full text or abstract was available for review. The variant NM_000249.4:c.2041G>A was not confirmed in this paper.Does not name this variant
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PMID 21120944 ↗Verification of the three-step model in assessing the pathogenicity of mismatchVerification of the three-step model for assessing MMR variant pathogenicity. MLH1 p.Ala681T was evaluated among 37 MLH1 variants. The variant was MMR proficient in vitro, with discrepant in silico results (one of two algorithms predicted pathogenicity). Under the three-step model, pathogenicity was not confirmed by STEP3 expression/localization assays in this 2011 study. This assessment was later superseded by more comprehensive clinical and expression defect data in PMID:23403630.Names this variant
Quoted passage
four variants (p.K618A, p.Y646C, p.A681T, and p.R687W), in which the STEP2 differences are due to an indication of pathogenicity by only one in silico assay, the pathogenicity is not confirmed by STEP3.
Results section, Verification of the Three-Step Model with MLH1 Variations
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PMID 21642682 ↗Cancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes inCancer risks associated with germline mutations in MLH1, MSH2, and MSH6 genes. No full text or abstract was available for review. The variant NM_000249.4:c.2041G>A was not confirmed in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 1,614,098 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
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 ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1564688410
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000249.4%3Ac.2041G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-37090446-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-37048955-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-37048955-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000249.4%3Ac.2041…
- OncoKB ↗www.oncokb.org/gene/MLH1/A681T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MLH1+c.2041G%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= 1.85862e-06; MAF= 0.00019%, 3/1614098 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66644e-05; MAF= 0.00167%, 1/60008 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is present in ClinVar (Variation ID: 17099); submission details unavailable.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.831. BayesDel score = 0.470252. HCI prior probability for pathogenicity = 0.0273. MAPP score = 8.22. Custom PP2 score = 0.198.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Inconclusive; curated oncogenicity label: Inconclusive.
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.