About ERCC2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ERCC2 c.298G>C, p.(Glu100Gln)
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
PM2Supporting
PM2 · supporting
This variant is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency 0%, well below the <0.1% threshold for PM2 under generic ACMG/AMP).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no deleterious effect. REVEL score 0.332 (below 0.5 pathogenic threshold), BayesDel score -0.154255 (negative, supporting benign effect), and SpliceAI max delta 0.01 (no predicted splicing alteration). The aggregate in silico prediction supports 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: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
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 did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ERCC2, a DNA helicase involved in the nucleotide excision repair (NER) pathway, is frequently altered in bladder cancer. Germline mutations of ERCC2 a
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: 2 met · 21 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000400.3:c.298G>C (p.Glu100Gln) in ERCC2 is a missense variant absent from all population databases (gnomAD v2.1, v4.1; PM2_supporting). Multiple in silico tools predict a benign effect (REVEL 0.332, BayesDel -0.154255, SpliceAI max delta 0.01; BP4_supporting). The variant is absent from ClinVar and has not been reported in the literature, and no functional data exist. One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, yielding a classification of Uncertain Significance (VUS) under generic ACMG/AMP 2015 rules (PMID:25741868).
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency 0%, well below the <0.1% threshold for PM2 under generic ACMG/AMP). Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF = 0%)
- gnomAD v4.1: absent (AF = 0%)
- gnomAD-Canada v1.0: absent (AF = 0%)
Sources
BP4 SupportingMultiple lines of computational evidence suggest no deleterious effect. REVEL score 0.332 (below 0.5 pathogenic threshold), BayesDel score -0.154255 (negative, supporting benign effect), and SpliceAI max delta 0.01 (no predicted splicing alteration). The aggregate in silico prediction supports a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.332 (<0.5 threshold)
- BayesDel: -0.154255 (negative score)
- SpliceAI: max delta 0.01 (no splicing impact)
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No evidence of a different nucleotide change at codon 100 resulting in the same amino acid substitution (p.Glu100Gln) that has been established as pathogenic. The variant is absent from ClinVar with no entries for any nucleotide change at this codon. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no comparator nucleotide changes at codon 100 identified
Still missing
- No ClinVar entries for any other nucleotide change producing p.Glu100Gln
Sources
PS2 No de novo data available. No parental testing or family studies have been reported for this variant. Details ▾Hide ▴
Still missing
- No de novo observation reported in literature or databases
PS3 No functional studies have been performed on NM_000400.3:c.298G>C (p.Glu100Gln). OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional evidence. No publications were identified that experimentally characterize this variant, and the variant does not fall within a systematically characterized range from any saturation mutagenesis or tiling screen. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence curated
Still missing
- No functional studies (in vitro or in vivo) performed on this variant
- No systematic mutagenesis data covering codon 100
Sources
PS4 No case-control or cohort data available. The variant has not been reported in affected individuals in ClinVar, COSMIC, or the literature. Details ▾Hide ▴
Evidence considered
- ClinVar: absent (no submitter entries)
- COSMIC: absent (no somatic cancer reports)
Still missing
- No affected vs. control prevalence data available
Sources
PM1 Codon 100 (p.Glu100Gln) is not located within a statistically significant mutational hotspot per cancerhotspots.org. No literature evidence establishes this residue as part of a critical functional domain in ERCC2. The OncoKB gene-level summary indicates ERCC2 is involved in NER but provides no domain mapping for codon 100. Details ▾Hide ▴
Evidence considered
- CancerHotspots: no hotspot at residue E100
- OncoKB: no domain-level functional annotation at codon 100
Still missing
- No domain characterization for codon 100 in the literature
Sources
PM6 No de novo data available. No publications report a de novo occurrence of this variant with confirmed or unconfirmed parentage. Details ▾Hide ▴
Still missing
- No de novo reports in literature or databases
PP1 No co-segregation data available. No family studies have been reported for this variant. Details ▾Hide ▴
Still missing
- No family co-segregation data
PP2 No gene-level missense constraint metric (e.g., missense Z-score, HCI prior) was retrieved for ERCC2 to support PP2. While ERCC2 missense variants are a known disease mechanism, the requisite constraint data is unavailable in the evidence packet. Details ▾Hide ▴
Evidence considered
- HCI Prior: not found for ERCC2 (gene not supported)
Still missing
- No missense Z-score or constraint metric available for ERCC2
PP3 Multiple lines of computational evidence do NOT support a deleterious effect. REVEL score 0.332 (below the 0.5 pathogenic threshold), BayesDel score -0.154255 (negative, benign-leaning), and SpliceAI max delta score 0.01 (no predicted splicing impact). The aggregate in silico prediction is not supportive of pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.332 (<0.5 threshold)
- BayesDel: -0.154255 (negative score)
- SpliceAI: max delta 0.01 (no splicing impact)
Sources
PP4 No patient phenotype information is available to assess clinical specificity for an ERCC2-associated disorder. Details ▾Hide ▴
Still missing
- No patient phenotype data provided
PP5 This variant is absent from ClinVar. No reputable source has classified it as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: absent (no classification by any submitter)
Still missing
- No ClinVar classification available
Sources
BA1 Variant is absent from gnomAD (allele frequency 0%), which does not meet the >1% threshold for BA1 under generic ACMG/AMP. Details ▾Hide ▴
BS1 Variant is absent from gnomAD (allele frequency 0%), which does not meet the >0.3% threshold for BS1 under generic ACMG/AMP. Details ▾Hide ▴
BS2 Variant is absent from gnomAD. No observations in healthy adults, either in heterozygous or homozygous state, have been reported. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
Still missing
- No observation in healthy adults to support benign classification
Sources
BS3 No functional studies demonstrating a benign effect have been reported for this variant. No literature evidence supports normal protein function for p.Glu100Gln. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional characterization
Still missing
- No functional assays (e.g.
- helicase activity
- NER assay) performed on this variant
Sources
BS4 No segregation data available. No family studies have been reported for this variant. Details ▾Hide ▴
Still missing
- No family segregation data
BP1 ERCC2-associated disease (trichothiodystrophy, xeroderma pigmentosum, Cockayne syndrome) is caused by both missense and truncating variants. BP1 is not applicable to genes where missense variants are an established disease mechanism. Details ▾Hide ▴
Evidence considered
- ERCC2 missense variants are established causes of TTD and XP per literature
BP2 No phase information available. No observation of this variant in trans with a known pathogenic variant in ERCC2 has been reported. Details ▾Hide ▴
Still missing
- No trans phase data with a pathogenic variant
BP5 No alternate molecular basis for disease has been identified in the case data provided. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis identified
BP6 This variant is absent from ClinVar. No reputable source has classified it as benign. Details ▾Hide ▴
Evidence considered
- ClinVar: absent (no classification by any submitter)
Still missing
- No ClinVar benign classification available
Sources
PS5 No evidence of a different pathogenic missense change at codon 100. ClinVar contains no entries for any missense variant at this residue for comparison. Details ▾Hide ▴
Evidence considered
- ClinVar: no entries for any amino acid change at codon 100
Still missing
- No pathogenic comparator at same residue
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000400.3:c.298G>C is a missense variant (p.Glu100Gln). The generic PVS1 framework (PMC6185798) applies only to null variants (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, single/multi-exon deletion). This variant does not fall into any of those buckets. Details ▾Hide ▴
Evidence considered
- Variant bucket: other (missense substitution)
- apply_generic_pvs1_framework: false per automated PVS1 variant assessment
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ANo phase information available for recessive disorder assessment; variant is absent from population databases, precluding trans analysis. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AVariant is a missense substitution, not an in-frame deletion/insertion or stop-loss variant causing protein length change. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue comparator variants identified. The PM5 candidate search could not confirm classic same-residue PM5 semantics; no ClinVar entries exist for any missense change at codon 100. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates found
- ClinVar: no entries at codon 100
Still missing
- No pathogenic comparator missense variant at codon 100
Sources
pm5_candidates
BP3 N/AVariant is a single-nucleotide substitution, not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (p.Glu100Gln), not a synonymous variant. BP7 applies only to synonymous variants affecting a non-conserved nucleotide with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Variant type: missense substitution
- not synonymous
Identifiers
- Gene
- ERCC2
- Transcript
- NM_000400.3
- Coding (HGVS c.)
- NM_000400.3:c.298G>C
- Protein (HGVS p.)
- NP_000391.1:p.(Glu100Gln)
- GRCh38
- chr19:45368692 C>G
- GRCh37
- chr19:45871950 C>G
Gene diagram
Every interpreted variant in ERCC2, mapped onto the exon structure of NM_000400.3. Select a row to find it on the plot.
ERCC2NM_000400.3
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 ERCC2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.332
- BayesDel
- -0.154
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no deleterious effect. REVEL score 0.332 (below 0.5 pathogenic threshold), BayesDel score -0.154255 (negative, supporting benign effect), and SpliceAI max delta 0.01 (no predicted splicing alteration). The aggregate in silico prediction supports a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.332 (<0.5 threshold)
- BayesDel: -0.154255 (negative score)
- SpliceAI: max delta 0.01 (no splicing impact)
Sources
PP3 Multiple lines of computational evidence do NOT support a deleterious effect. REVEL score 0.332 (below the 0.5 pathogenic threshold), BayesDel score -0.154255 (negative, benign-leaning), and SpliceAI max delta score 0.01 (no predicted splicing impact). The aggregate in silico prediction is not supportive of pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.332 (<0.5 threshold)
- BayesDel: -0.154255 (negative score)
- SpliceAI: max delta 0.01 (no splicing impact)
Sources
BP7 N/AThis is a missense variant (p.Glu100Gln), not a synonymous variant. BP7 applies only to synonymous variants affecting a non-conserved nucleotide with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Variant type: missense substitution
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.332. BayesDel score = -0.154255.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
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 ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000400.3%3Ac.298G%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-45871950-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-45368692-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-45368692-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000400.3%3Ac.298G…
- OncoKB ↗www.oncokb.org/gene/ERCC2/E100Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ERCC2+c.298G%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.332. BayesDel score = -0.154255.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ERCC2, a DNA helicase involved in the nucleotide excision repair (NER) pathway, is frequently altered in bladder cancer. Germline mutations of ERCC2 a
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.