NM_000400.3:c.298G>C

ERCC2 · NP_000391.1:p.(Glu100Gln) · NM_000400.3

GRCh37: chr19:45871950 C>G · GRCh38: chr19:45368692 C>G

Gene: ERCC2 Transcript: NM_000400.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

ERCC2

Transcript

NM_000400.3

Protein

NP_000391.1:p.(Glu100Gln)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	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.	clinvar
PS2	Not met	No de novo data available. No parental testing or family studies have been reported for this variant.
PS3	Not met	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.	oncokb
PS4	Not met	No case-control or cohort data available. The variant has not been reported in affected individuals in ClinVar, COSMIC, or the literature.	clinvar
PS5	Not met	No evidence of a different pathogenic missense change at codon 100. ClinVar contains no entries for any missense variant at this residue for comparison.	clinvar
PM1	Not met	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.	oncokb
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	N/A	No 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.	pm5_candidates
PM6	Not met	No de novo data available. No publications report a de novo occurrence of this variant with confirmed or unconfirmed parentage.
PP1	Not met	No co-segregation data available. No family studies have been reported for this variant.
PP2	Not met	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	No patient phenotype information is available to assess clinical specificity for an ERCC2-associated disorder.
PP5	Not met	This variant is absent from ClinVar. No reputable source has classified it as pathogenic.	clinvar
BA1	Not met	Variant is absent from gnomAD (allele frequency 0%), which does not meet the >1% threshold for BA1 under generic ACMG/AMP.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from gnomAD (allele frequency 0%), which does not meet the >0.3% threshold for BS1 under generic ACMG/AMP.	gnomad_v2 gnomad_v4
BS2	Not met	Variant is absent from gnomAD. No observations in healthy adults, either in heterozygous or homozygous state, have been reported.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrating a benign effect have been reported for this variant. No literature evidence supports normal protein function for p.Glu100Gln.	oncokb
BS4	Not met	No segregation data available. No family studies have been reported for this variant.
BP1	Not met	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.
BP2	Not met	No phase information available. No observation of this variant in trans with a known pathogenic variant in ERCC2 has been reported.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No alternate molecular basis for disease has been identified in the case data provided.
BP6	Not met	This variant is absent from ClinVar. No reputable source has classified it as benign.	clinvar
BP7	N/A	This 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.
BP3	N/A	Variant is a single-nucleotide substitution, not an in-frame deletion or insertion in a repetitive region.
PM3	N/A	No phase information available for recessive disorder assessment; variant is absent from population databases, precluding trans analysis.
PM4	N/A	Variant is a missense substitution, not an in-frame deletion/insertion or stop-loss variant causing protein length change.

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