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ERCC2
Final classification
VUS
ERCC2 c.298G>C · p.Glu100Gln
ERCC2

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).

Gene
ERCC2
Transcript
NM_000400.3
HGVS · transcript:coding
NM_000400.3:c.298G>C
Consequence
N/A
GRCh38
chr19:45368692 C>G
GRCh37
chr19:45871950 C>G
Basis 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. ▾
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.
Classification rationale
PM2 BP4 VUS
ERCC2 c.298G>C

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).1

PM2 + BP4 → VUS
1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗revelbayesdelspliceai ↗clinvar ↗generic_acmg_combination_rules
Gene diagram · NM_000400.3 · variants mapped to exon structure
ERCC2 NM_000400.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength Supporting Moderate Strong Very strong
✓
PM2 supporting Pathogenic
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).
gnomAD v2.1: absent (AF = 0%)gnomAD v4.1: absent (AF = 0%)gnomAD-Canada v1.0: absent (AF = 0%)
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
✓
BP4 supporting Benign
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.
REVEL: 0.332 (<0.5 threshold)BayesDel: -0.154255 (negative score)SpliceAI: max delta 0.01 (no splicing impact)
spliceai ↗
Assessed · not applied
Pathogenic
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.
PS2 No de novo data available.
PS3 No functional studies have been performed on NM_000400.3:c.298G>C (p.Glu100Gln).
PS4 No case-control or cohort data available.
PM1 Codon 100 (p.Glu100Gln) is not located within a statistically significant mutational hotspot per cancerhotspots.org.
PM6 No de novo data available.
PP1 No co-segregation data available.
PP2 No gene-level missense constraint metric (e.g., missense Z-score, HCI prior) was retrieved for ERCC2 to support PP2.
PP3 Multiple lines of computational evidence do NOT support a deleterious effect.
PP4 No patient phenotype information is available to assess clinical specificity for an ERCC2-associated disorder.
PP5 This variant is absent from ClinVar.
Benign
BA1 Variant is absent from gnomAD (allele frequency 0%), which does not meet the >1% threshold for BA1 under generic ACMG/AMP.
BS1 Variant is absent from gnomAD (allele frequency 0%), which does not meet the >0.3% threshold for BS1 under generic ACMG/AMP.
BS2 Variant is absent from gnomAD.
BS3 No functional studies demonstrating a benign effect have been reported for this variant.
BS4 No segregation data available.
BP1 ERCC2-associated disease (trichothiodystrophy, xeroderma pigmentosum, Cockayne syndrome) is caused by both missense and truncating variants.
BP2 No phase information available.
BP5 No alternate molecular basis for disease has been identified in the case data provided.
BP6 This variant is absent from ClinVar.
N/A · 6 PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.332. BayesDel score = -0.154255.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
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
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots