LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-30
Case ID: NM_001127511.2_c.78C_A_20260930_202018
Framework: ACMG/AMP 2015
Variant classification summary

NM_001127511.2:c.78C>A

APC  · NP_001120983.2:p.(Ser26Arg)  · NM_001127511.2
GRCh37: chr5:112043492 C>A  ·  GRCh38: chr5:112707795 C>A
Gene: APC Transcript: NM_001127511.2
Final call
Benign
BA1 stand-alone benign BS1 strong BS2 strong BP1 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
APC
Transcript
NM_001127511.2
Protein
NP_001120983.2:p.(Ser26Arg)
gnomAD AF
0.0016634346423396646 (v4.1)
ClinVar
Benign
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BA1 stand-alone benign: non-cancer gnomAD v2.1.1 popmax filtering AF 2.78% is about 28-fold above the APC VCEP 0.1% threshold, which alone establishes Benign.
2
BS1 strong: the same 2.78% popmax filtering AF is roughly 2,780-fold above the 0.001% threshold, though subsumed by BA1.
3
BS2 strong: the APC VCEP homozygous-state clause is met, with 18 homozygotes in gnomAD v3.1 non-cancer genomes and 33 in v4.1 against a requirement of 2.
4
BP1 supporting: a missense change at codon 26, outside the VCEP's excluded beta-catenin repeat (codons 1021-1035), in a gene where over 90% of pathogenic variants truncate.
Final determination: Rule26 of the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel APC specification v2.1: one Benign Stand Alone criterion (BA1) is sufficient for a Benign classification, and BA1 is met here by the 2.78% non-cancer gnomAD popmax filtering allele frequency.
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.78C>A is the missense change p.(Ser26Arg), not an APC null variant, so no PVS1 strength tier applies.
cspec vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 vcep_apc_specifications_supplementary_material_v2 spliceai PMID:25741868
PS1 Not met Not met: APC-specific PS1 applies only to the two Likely Pathogenic missense residues, 1026 and 1028; this variant changes Ser26, where no pathogenic missense is established.
cspec vcep_apc_specifications_supplementary_material_v2 clinvar spliceai
PS2 Not assessed Not assessed: no proband or parental testing exists in this case, so no APC VCEP de novo score (1-1.5 for PS2_Moderate) can be counted.
cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 clinvar
PS3 Not assessed Not assessed: no functional assay exists for p.(Ser26Arg), and the VCEP protein-assay route covers only codons 959-2129, not codon 26.
cspec vcep_apc_specifications_supplementary_material_v2 vcep_apc_rules_for_combining_criteria_v2 clinvar
PS4 Not assessed Not assessed: no proband phenotype or family history was available to curate APC VCEP Table 1 phenotype points, and no case-control enrichment exists for this variant.
cspec vcep_table_1_262 clinvar PMID:24728327
PM1 N/A Not applicable: the APC VCEP excludes PM1 at all strengths, stating no mutational hotspots for pathogenic germline missense variants are known in APC.
cspec vcep_apc_specifications_supplementary_material_v2
PM2 Not met Not met: non-cancer gnomAD v2.1.1 allele frequency 0.186% is roughly 620-fold above the APC VCEP PM2 threshold of 0.0003%.
cspec gnomad_v2 gnomad_v4
PM3 N/A Not applicable: the APC VCEP does not use PM3 because FAP is inherited in an autosomal dominant, not recessive, pattern.
cspec vcep_apc_specifications_supplementary_material_v2
PM4 N/A Not applicable: the APC VCEP does not use PM4, and p.(Ser26Arg) alters no protein length - it is a substitution, not an in-frame indel or stop-loss.
cspec vcep_apc_specifications_supplementary_material_v2 PMID:25741868
PM5 Not met Not met: APC-specific PM5 is restricted to residues 1026 and 1028, and no same-residue missense comparator exists at Ser26.
cspec vcep_apc_specifications_supplementary_material_v2 pm5_candidates clinvar
PM6 Not assessed Not assessed: no assumed-de-novo observation or parentage data are recorded, so no APC VCEP de novo score (0.5 for PM6_Supporting) can be counted.
cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 clinvar
PP1 Not assessed Not assessed: zero genotyped relatives and zero meioses are documented, versus the APC VCEP Supporting threshold of 3-4 meioses in one family.
cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 clinvar
PP2 N/A Not applicable: the APC VCEP does not use PP2, since missense variants are not a frequent APC mutation type and only residues 1026 and 1028 carry Likely Pathogenic missense.
cspec vcep_apc_specifications_supplementary_material_v2
PP3 Not met Not met: SpliceAI max delta 0.007 falls below the 0.2 supporting threshold, predicting no deleterious splice effect.
cspec spliceai revel bayesdel
PP4 N/A Not applicable: the APC VCEP retires PP4, its phenotype-specificity content already captured by the PS4 phenotype-point scheme.
cspec vcep_apc_specifications_supplementary_material_v2
PP5 N/A Not applicable: the APC VCEP does not use PP5, and ClinVar variation 133505 has zero expert-panel submissions across its ten submitters.
cspec clinvar vcep_apc_specifications_supplementary_material_v2
BA1 Met Met: non-cancer gnomAD v2.1.1 popmax filtering AF 2.78%, about 28-fold above the 0.1% APC VCEP stand-alone BA1 threshold.
cspec gnomad_v2 gnomad_v4
BS1 Met Met: the same 2.78% non-cancer gnomAD popmax filtering AF far exceeds the APC VCEP BS1 threshold of 0.001%, though subsumed by BA1.
cspec gnomad_v2 gnomad_v4
BS2 Met Met: 18 homozygotes in gnomAD v3.1 non-cancer genomes and 33 in v4.1 exceed the APC VCEP >=2 homozygous-state requirement.
cspec gnomad_v2 gnomad_v4 gnomad_canada
BS3 Not assessed Not assessed: no RNA or beta-catenin-activity assay exists, and VCEP BS3 evidence is limited to synonymous/intronic RNA assays or codons 959-2129.
cspec vcep_apc_specifications_supplementary_material_v2 vcep_apc_rules_for_combining_criteria_v2 clinvar
BS4 Not assessed Not assessed: no affected relative lacking the variant is documented, so the APC VCEP BS4 phenotype-point thresholds (0.5-1 point) cannot be applied.
cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 clinvar
BP1 Met Met at supporting: this missense lies at codon 26, outside the VCEP's excluded beta-catenin repeat (codons 1021-1035), in a gene where over 90% of pathogenic variants truncate.
cspec vcep_apc_specifications_supplementary_material_v2 spliceai PMID:21368914
BP2 Not met Not met: no report of c.78C>A in trans with a pathogenic APC variant and zero unknown-phase co-occurrences versus the required three.
cspec clinvar
BP3 N/A Not applicable: the APC VCEP excludes BP3, and p.(Ser26Arg) is a missense substitution, not an in-frame indel in a repeat region.
cspec vcep_apc_specifications_supplementary_material_v2 PMID:25741868
BP4 N/A Not applicable: the APC VCEP excludes BP4 for missense variants, and c.78C>A is the missense change p.(Ser26Arg).
cspec
BP5 Not assessed Not assessed: no colorectal polyposis phenotype record and no other-gene testing results were available to establish or exclude an alternate genetic basis.
cspec vcep_apc_specifications_supplementary_material_v2
BP6 N/A Not applicable: the APC VCEP does not use BP6, and ClinVar variation 133505 has zero expert-panel submissions asserting any classification.
cspec clinvar vcep_apc_specifications_supplementary_material_v2
BP7 N/A Not applicable: BP7 requires a synonymous or qualifying intronic variant, whereas c.78C>A is the missense change p.(Ser26Arg).
cspec
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