NM_003537.3:c.244G>C (p.Asp82His) is a missense variant in H3C2, a histone H3 gene recurrently altered in pediatric cancers including glioblastoma.1 The variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).2 The variant is not present in COSMIC and does not lie within a statistically significant mutational hotspot. In silico predictions are equivocal: REVEL score is 0.585 and BayesDel is 0.631, both borderline toward pathogenicity, while SpliceAI predicts no splicing impact (max delta 0.08).3 No functional studies, segregation data, de novo reports, or case-control evidence have been identified for this variant. OncoKB reports no variant-specific functional evidence.4 A single ClinVar submission from Invitae classifies the variant as uncertain significance; no expert panel or multi-submitter consensus is available.5 Only one supporting pathogenic criterion (PM2_Supporting) is met. No benign criteria are met. The evidence is insufficient to classify the variant as pathogenic or benign.6
H3C2
Final classification
VUS
H3C2 c.244G>C · p.Asp82His
H3C2
NM_003537.3:c.244G>C (p.Asp82His) is a missense variant in H3C2, a histone H3 gene recurrently altered in pediatric cancers including glioblastoma.
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; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
H3C2 c.244G>C
PM2
→
VUS
Gene diagram
· NM_003537.3 · variants mapped to exon structure
H3C2
NM_003537.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 22 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_003537.3:c.244G>C is absent from gnomAD v2.1 (exomes) and v4.1 (exomes/genomes), as well as gnomAD-Canada v1.0. The allele frequency is 0.0 in all population databases queried, supporting a pathogenic role under PM2.
Absent from gnomAD v2.1 (AC=0AN=null — no coverage at this position) and absent from gnomAD v4.1 (AC=0). Also absent from gnomAD-Canada v1.0.
Assessed · not applied
Pathogenic
PS1
No established pathogenic variant causing the same amino acid change (p.Asp82His) via a different nucleotide substitution has been identified in ClinVar, the literature, or other evidence sources.
PS2
No de novo occurrence of NM_003537.3:c.244G>C has been reported.
PS3
No direct functional studies of the H3C2 p.Asp82His substitution have been published.
PS4
Insufficient data to evaluate case-control enrichment.
PM1
Residue Asp82 lies within the histone fold domain (residues ~45-135), but codon 82 is not a statistically significant mutational hotspot in cancer (Cancer Hotspots database) or germline disease.
PM5
No different missense change at H3C2 codon 82 (Asp82) has been classified as pathogenic.
PM6
No de novo reports exist for NM_003537.3:c.244G>C.
PP1
No familial co-segregation data are available for NM_003537.3:c.244G>C.
PP2
PP2 requires a gene with a low rate of benign missense variation where missense is a common mechanism of disease.
PP3
In silico predictions are borderline and do not provide multiple consistent lines of computational evidence supporting a deleterious effect.
PP4
No clinical phenotype or family history data specific to this variant are available.
PP5
No reputable source has classified NM_003537.3:c.244G>C as pathogenic.
Benign
BA1
NM_003537.3:c.244G>C is absent from gnomAD v2.1 and v4.1 (allele frequency = 0).
BS1
NM_003537.3:c.244G>C is absent from gnomAD v2.1 and v4.1 (allele frequency = 0).
BS2
The variant has not been observed in any individual, healthy or affected.
BS3
No functional studies demonstrating that the p.Asp82His substitution has no deleterious effect on protein function have been identified.
BS4
No segregation data demonstrating non-segregation of NM_003537.3:c.244G>C with disease are available.
BP1
BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease.
BP2
The variant has not been observed in any individual, so co-occurrence in trans with a known pathogenic variant cannot be assessed.
BP4
Multiple lines of computational evidence do not support a benign impact.
BP5
No evidence exists that an alternate molecular basis for disease has been identified in any individual carrying NM_003537.3:c.244G>C.
BP6
No reputable source has classified NM_003537.3:c.244G>C as benign.
N/A · 2
PVS1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.08). REVEL score = 0.585. BayesDel score = 0.631182.
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. H3C2, a histone variant, is recurrently altered by mutation in various pediatric cancers, including pediatric glioblastoma.
COSMIC
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.
Sources & reference links