LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-18
Case ID: NM_001127510.3_c.6907G_A_20260918_192556
Framework: ACMG/AMP 2015
Variant classification summary

NM_001127510.3:c.6907G>A

APC  · NP_001120982.1:p.(Gly2303Arg)  · NM_001127510.3
GRCh37: chr5:112178198 G>A  ·  GRCh38: chr5:112842501 G>A
Gene: APC Transcript: NM_001127510.3
Final call
Benign
BA1 stand-alone benign BS1 strong BP1 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
APC
Transcript
NM_001127510.3
Protein
NP_001120982.1:p.(Gly2303Arg)
gnomAD AF
0.00015738195733585805 (v4.1)
ClinVar
Likely benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BA1 (stand-alone benign): gnomAD v2.1 non-cancer Popmax filtering AF 0.216% (80/30,518 South Asian alleles) exceeds the APC VCEP 0.1% stand-alone threshold, which alone yields Benign.
2
BS1 (strong): the same non-cancer frequency clears the APC VCEP 0.001% strong-benign bar, but it rests on the same observation as BA1 and adds no independent weight.
3
BP1 (supporting): missense p.(Gly2303Arg) at codon 2303 sits outside the VCEP's codon 1021-1035 exception in a gene where >90% of pathogenic point mutations are truncating.
Final determination: Under the APC VCEP v2.1 criteria-combination rules, BA1 alone satisfies Rule26 in the Benign.Stand Alone partition, which maps to Benign.
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 Not met Not met: c.6907G>A causes a missense change, p.(Gly2303Arg), not a null variant, so the APC VCEP PVS1 decision tree is never triggered.
cspec vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 pvs1_gene_context pvs1_generic_framework spliceai
PS1 Not met Not met: no established pathogenic or likely pathogenic APC variant produces p.(Gly2303Arg); the VCEP recognises only p.(Asn1026Ser) and p.(Ser1028Arg) as likely pathogenic missense changes.
cspec clinvar
PS2 Not assessed Not assessed: with no proband, parental testing, or de novo observation recorded, the APC de novo score of at least 1 required for PS2 cannot be computed.
cspec vcep_table_1_262 vcep_apc_specifications_supplementary_material_v2 clinvar
PS3 Not met Not met: no functional assay exists for p.(Gly2303Arg), and the APC VCEP protein-assay route excludes codon 2303, outside codons 959-2129.
cspec vcep_apc_specifications_supplementary_material_v2 oncokb
PS4 Not assessed Not assessed: no proband carrying this variant has documented phenotype points, versus PS4 thresholds of >=16 (very strong) down to 1 (supporting).
cspec vcep_table_1_262 vcep_apc_specifications_supplementary_material_v2 clinvar
PM1 N/A Not applicable: APC VCEP v2.1 designates PM1 not applicable, and residue 2303 lies outside the beta-catenin binding domain (codons 959-2129) with no hotspot.
cspec PMID:21368914
PM2 Not met Not met: gnomAD v2.1 non-cancer AF 0.0351% (83/236,496 alleles) exceeds the APC VCEP PM2 threshold of 0.0003% (0.000003) by about 117-fold.
cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2
PM3 N/A Not applicable: the InSiGHT APC VCEP (v2.1) excludes PM3 outright because FAP is inherited in an autosomal-dominant, not recessive, pattern.
cspec vcep_apc_specifications_supplementary_material_v2 PMID:25741868 PMID:25645574
PM4 N/A Not applicable: the APC VCEP does not use PM4, and this single-base missense change leaves protein length unchanged at 2,843 residues.
cspec vcep_apc_specifications_supplementary_material_v2
PM5 Not met Not met: no pathogenic or likely pathogenic missense variant exists at residue 2303; the VCEP's only established missense comparators sit at codons 1026 and 1028.
cspec clinvar pm5_candidates
PM6 Not assessed Not assessed: no assumed-de novo proband observation is recorded, so the minimum de novo score of 0.5 needed for PM6_Supporting cannot be derived.
cspec vcep_table_1_262 vcep_apc_specifications_supplementary_material_v2 clinvar
PP1 Not assessed Not assessed: no pedigree or meiosis data exists for any family, against the APC PP1_Supporting minimum of 3-4 segregating meioses in one family.
cspec clinvar
PP2 N/A Not applicable: the APC VCEP designates PP2 not applicable because APC disease is driven predominantly by truncating variants, not pathogenic missense variation.
cspec PMID:21368914
PP3 Not met Not met: the missense-applicable REVEL score 0.611 falls below the 0.644 PP3-supporting threshold, and the VCEP-required SpliceAI splice result was unavailable.
cspec revel spliceai bayesdel
PP4 N/A Not applicable: the APC VCEP excludes PP4 because phenotype specificity is already captured by its PS4 phenotype-point system.
cspec vcep_apc_specifications_supplementary_material_v2
PP5 Not met Not met: the exact-variant ClinVar record has zero expert-panel Pathogenic/Likely pathogenic submissions (all 15 are ordinary single-submitter laboratories).
clinvar cspec PMID:25741868
BA1 Met Met: gnomAD v2.1 non-cancer Popmax FAF 0.216% (0.00216) exceeds the APC VCEP BA1 stand-alone threshold of 0.1% (0.001), driven by South Asian alleles.
cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2 gnomad_v4 PMID:25645574
BS1 Met Met: gnomAD v2.1 non-cancer Popmax FAF 0.216% (0.00216) far exceeds the APC VCEP BS1 strong threshold of 0.001% (0.00001), but BA1 supersedes it.
cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2 gnomad_v4
BS2 Not met Not met: 1 homozygote in gnomAD v2.1 non-cancer, the VCEP-specified source, versus the >= 2 homozygotes required for BS2 strong.
cspec vcep_apc_specifications_supplementary_material_v2 gnomad_v2 gnomad_v4 PMID:24728327
BS3 Not met Not met: BS3 needs an RNA or beta-catenin protein assay this missense variant at codon 2303 lacks, codons 959-2129 being the framework limit.
cspec vcep_apc_specifications_supplementary_material_v2 oncokb
BS4 Not assessed Not assessed: no affected relative tested or reported without the variant, against the BS4 minimum of one affected non-carrier scoring at least 0.5 phenotype points.
cspec vcep_table_1_262 clinvar
BP1 Met Met at supporting strength: missense p.(Gly2303Arg) at codon 2303 sits outside the VCEP's codon 1021-1035 exception in a gene where truncating variants predominate.
cspec PMID:21368914 PMID:25645574 PMID:25741868
BP2 Not met Not met: no in-trans or >=3 unknown-phase co-occurrence with a (likely) pathogenic APC variant is reported for c.6907G>A.
cspec vcep_apc_specifications_supplementary_material_v2 clinvar gnomad_v4 PMID:25741868
BP3 N/A Not applicable: the APC VCEP does not use BP3, which covers repeat-region in-frame indels, not this single-base missense change.
cspec
BP4 N/A Not applicable: the APC VCEP excludes BP4 for missense variants, and REVEL 0.611 would also exceed the generic BP4-supporting cutoff of 0.29.
cspec revel
BP5 Not assessed Not assessed: no alternate-gene (POLD1/POLE/MUTYH/NTHL1/MSH3/MMR) pathogenic finding or colorectal polyposis phenotype is documented to satisfy the categorical BP5 rule.
cspec vcep_apc_specifications_supplementary_material_v2
BP6 Not met Not met: benign/likely benign exact-variant ClinVar assertions come only from ordinary single-submitter laboratories (zero expert-panel submissions), so BP6 is not triggered.
clinvar cspec PMID:25741868
BP7 N/A Not applicable: BP7 requires a synonymous or intronic variant, whereas c.6907G>A is a coding missense change (p.Gly2303Arg).
cspec
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