NM_003537.3:c.244G>C

H3C2 · NP_003528.1:p.(Asp82His) · NM_003537.3

GRCh37: chr6:26032045 C>G · GRCh38: chr6:26031817 C>G

Gene: H3C2 Transcript: NM_003537.3

Final call

VUS

PM2 supporting

Variant details

Gene

H3C2

Transcript

NM_003537.3

Protein

NP_003528.1:p.(Asp82His)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

The variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).

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).

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.

A single ClinVar submission from Invitae classifies the variant as uncertain significance; no expert panel or multi-submitter consensus is available.

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.

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	PVS1 is not applicable to missense variants. NM_003537.3:c.244G>C is a missense change (p.Asp82His) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required by the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	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.	clinvar
PS2	Not met	No de novo occurrence of NM_003537.3:c.244G>C has been reported. Targeted exploratory literature and ClinVar search identified no de novo designations for any missense at H3C2 codon 82.	clinvar
PS3	Not met	No direct functional studies of the H3C2 p.Asp82His substitution have been published. In vitro or in vivo functional characterization of this exact missense change is absent from the literature and curated databases including OncoKB.	oncokb
PS4	Not assessed	Insufficient data to evaluate case-control enrichment. The variant is absent from gnomAD population databases, and no affected individuals carrying this variant have been reported in disease cohorts or ClinVar (a single ClinVar submission classifies it as uncertain significance with no proband count).	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	No different missense change at codon 82 of H3C2 has been classified as pathogenic. There is no established pathogenic comparator at this residue to support PS5.	clinvar pm5_candidates
PM1	Not met	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. PM1 requires a mutational hotspot or a well-established critical functional domain without benign variation; Asp82 does not meet this threshold.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Not met	No different missense change at H3C2 codon 82 (Asp82) has been classified as pathogenic. The PM5 candidate search found zero same-residue comparators in ClinVar with pathogenic or likely pathogenic classification.	pm5_candidates
PM6	Not met	No de novo reports exist for NM_003537.3:c.244G>C. ClinVar contains no de novo assertion for this variant, and targeted literature search yielded no case reports with confirmed parentage testing.	clinvar
PP1	Not met	No familial co-segregation data are available for NM_003537.3:c.244G>C. No pedigrees with multiple affected carriers have been reported in ClinVar or the literature.	clinvar
PP2	Not assessed	PP2 requires a gene with a low rate of benign missense variation where missense is a common mechanism of disease. H3C2 missense constraint data (missense Z-score or missense observed/expected ratio) were not available in the evidence bundle. The gnomAD pLI of 0.00 and LOEUF of 0.85 reflect loss-of-function tolerance, which is distinct from missense constraint. This criterion cannot be assessed without a direct missense constraint metric.
PP3	Not met	In silico predictions are borderline and do not provide multiple consistent lines of computational evidence supporting a deleterious effect. REVEL score is 0.585 (marginally above the 0.5 threshold but below commonly used higher thresholds such as 0.75). BayesDel score is 0.631 (modestly in the pathogenic direction). SpliceAI predicts no splicing impact (max delta = 0.08). Taken together, the computational evidence is equivocal and does not meet the PP3 requirement.	revel bayesdel spliceai
PP4	Not met	No clinical phenotype or family history data specific to this variant are available. The variant has been reported only once in ClinVar (uncertain significance, no phenotype details provided), and no case reports describe the clinical presentation associated with NM_003537.3:c.244G>C.	clinvar
PP5	Not met	No reputable source has classified NM_003537.3:c.244G>C as pathogenic. The only ClinVar submission (Invitae, a single non-expert submitter) classifies it as uncertain significance, which does not meet the PP5 requirement for a reputable source asserting pathogenicity.	clinvar
BA1	Not met	NM_003537.3:c.244G>C is absent from gnomAD v2.1 and v4.1 (allele frequency = 0). The allele frequency is well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	NM_003537.3:c.244G>C is absent from gnomAD v2.1 and v4.1 (allele frequency = 0). The allele frequency is well below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	The variant has not been observed in any individual, healthy or affected. No data exist to support observation in a healthy adult with full penetrance expected at an early age.
BS3	Not met	No functional studies demonstrating that the p.Asp82His substitution has no deleterious effect on protein function have been identified. No in vitro or in vivo assays have been performed for this variant.
BS4	Not met	No segregation data demonstrating non-segregation of NM_003537.3:c.244G>C with disease are available. No family studies have been reported.
BP1	Not met	BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. For histone H3 genes (including H3C2), the known pathogenic mechanism involves missense mutations at specific residues (K27M, G34R/V, K36M in related paralogs), not truncating variants. Therefore BP1 does not apply.
BP2	Not met	The variant has not been observed in any individual, so co-occurrence in trans with a known pathogenic variant cannot be assessed. No data support BP2 application.
BP4	Not met	Multiple lines of computational evidence do not support a benign impact. REVEL (0.585) and BayesDel (0.631) both lean in the pathogenic direction, not benign. SpliceAI (max delta 0.08) predicts no splicing impact, but this alone is insufficient to meet BP4 when missense predictors suggest possible deleteriousness.	revel bayesdel spliceai
BP5	Not met	No evidence exists that an alternate molecular basis for disease has been identified in any individual carrying NM_003537.3:c.244G>C. The variant has not been observed in any case with a known pathogenic variant at another locus.
BP6	Not met	No reputable source has classified NM_003537.3:c.244G>C as benign. The only ClinVar submission classifies it as uncertain significance, which does not support BP6.	clinvar
BP7	N/A	BP7 is not applicable. NM_003537.3:c.244G>C is a missense variant (p.Asp82His), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact.

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