Variant classification summary

NM_000410.4:c.845G>A

HFE · NP_000401.1:p.(Cys282Tyr) · NM_000410.4

GRCh37: chr6:26093141 G>A · GRCh38: chr6:26092913 G>A

Gene: HFE Transcript: NM_000410.4

Final call

VUS

PS1 strong PS3 strong PP3 moderate BA1 stand-alone benign

Variant details

Gene

HFE

Transcript

NM_000410.4

Protein

NP_000401.1:p.(Cys282Tyr)

gnomAD AF

0.0569822579785817 (v4.1)

ClinVar

Pathogenic

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS1 strong because the identical p.Cys282Tyr change is reported in HFE-related hemochromatosis.

2

Pathogenic: PS3 strong because independent cellular and mouse studies show damaging HFE effects.

3

Pathogenic: PP3 moderate because REVEL 0.872 exceeds the 0.773 moderate threshold.

4

Benign: BA1 stand-alone because gnomAD v4.1 allele frequency 0.0569823 exceeds 0.05.

5

VUS: pathogenic and benign combination rules are both satisfied, creating conflicting evidence.

Final determination: Under generic ACMG/AMP 2015 rules, PS1 strong plus PS3 strong satisfies the pathogenic rule for two strong criteria, while BA1 independently satisfies the benign stand-alone rule; conflicting evidence results in VUS.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Met	Met at strong strength: the identical p.Cys282Tyr change accounts for more than 80% of Caucasian hemochromatosis cases in the cited cohort summary.	PMID:27518069 PMID:10575540
PS2	Not assessed	Not assessed: no documented proband phenotype, parental maternity and paternity testing, or family-history assessment is available.	clinvar
PS3	Met	Met, strong: independent cellular and mouse studies showed loss of beta-2-microglobulin interaction, absent surface expression, and altered HFE-dependent phenotypes for C282Y.	PMID:9162021 PMID:21243428 PMID:22531912
PS4	Not met	Not met: no affected-versus-control variant counts permit the required PS4 OR greater than 5.0 with a 95% CI excluding 1.0.	PMID:10575540 PMID:27518069 PMID:9162021
PM1	Not assessed	Not assessed: Cys282 is functionally important, but no qualifying HFE hotspot/domain and no benign-variation exclusion are established in the supplied evidence.	PMID:9162021
PM2	Not met	Not met: gnomAD v4.1 all-comers AF is 0.0569823 with 3,399 homozygotes, far above the <=0.0001 PM2 threshold.	gnomad_v4 gnomad_v2 PMID:25741868
PM3	Not assessed	Not assessed: two affected probands had C282Y in trans with G93R or S65C, but the partner variants are not independently established as pathogenic.	PMID:10575540
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense change at HFE residue Cys282 is identified in the supplied comparator data or paper extracts.	pm5_candidates
PM6	Not assessed	Not assessed: a database de novo label lacks a case report documenting the proband, family history, and unconfirmed parental origin.	clinvar
PP1	Not assessed	Not assessed: no affected-relative transmission count is reported; the available study shows variant phase, not cosegregation across multiple affected family members.	PMID:10575540
PP2	Not assessed	Not assessed: missense HFE disease variants are documented, but the supplied evidence lacks a gene-level benign-missense rate assessment.	PMID:10575540 PMID:27518069
PP3	Met	Met at moderate strength: REVEL 0.872 exceeds the generic PP3 moderate threshold of 0.773 for missense variants.	revel
PP4	Not assessed	Not assessed: the present case lacks phenotype or family-history details demonstrating a highly specific hereditary-hemochromatosis presentation.
PP5	Not met	Not met: ClinVar reports zero exact-variant expert-panel submissions, so ordinary pathogenic submissions cannot trigger PP5.	clinvar
BA1	Met	Met: gnomAD v4.1 all-comers allele frequency is 0.0569823, exceeding the >=0.05 BA1 stand-alone threshold.	gnomad_v4 gnomad_v2 PMID:25741868
BS1	Not assessed	Not assessed: AF 0.0569823 exceeds 1%, but no prevalence-, penetrance-, and allelic-heterogeneity-based maximum credible frequency was supplied.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD v4.1 reports 3,399 homozygotes, but population records do not establish healthy adults with full early-age penetrance.	gnomad_v4 gnomad_v2
BS3	Not met	Not met: C282Y abolished beta-2-microglobulin interaction and surface expression in HEK293 cells rather than showing no damaging effect on HFE function.	PMID:9162021 PMID:21243428 PMID:22531912
BS4	Not assessed	Not assessed: no affected non-carriers or pedigree-based non-segregation analysis is documented for this variant.
BP1	Not assessed	Not assessed: supplied HFE reports document missense disease variants but do not establish that truncating variants are the primary disease mechanism.	PMID:10575540 PMID:27518069
BP2	Not met	Not met: the reported phase is trans, whereas BP2 requires trans only for fully penetrant dominant disorders or cis in any inheritance pattern.	PMID:10575540
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.872 is above the generic BP4 supporting cutoff of 0.29 for missense variants.	revel
BP5	Not assessed	Not assessed: no case-specific alternate molecular basis for disease is documented alongside this variant.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign classification is present; the flagged OMIM record is not an expert-panel assertion.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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