Variant classification summary

NM_001127510.3:c.4893T>C

APC · NP_001120982.1:p.(Ser1631=) · NM_001127510.3

GRCh37: chr5:112176184 T>C · GRCh38: chr5:112840487 T>C

Gene: APC Transcript: NM_001127510.3

Final call

Benign

BA1 stand-alone benign BS1 strong BS2 strong BP1 supporting BP4 supporting BP7 supporting

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(Ser1631=)

gnomAD AF

0.0004683562183580769 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 stand-alone benign: gnomAD popmax filtering AF 0.85% (v4.1) and 0.73% (v2.1) exceed the APC VCEP threshold of 0.1%, which by itself makes the variant Benign.

2

BS1 strong: the same popmax filtering AFs exceed the APC VCEP BS1 threshold of 0.001% by over two orders of magnitude, but are subsumed by BA1.

3

BS2 strong: 9 homozygotes in gnomAD v4.1 (and 4 in v3.1 non-cancer genomes) meet the >=2 homozygotes clause.

4

BP1 supporting: APC disease is driven by truncating variants, and this synonymous change at codon 1631 is outside the excluded missense region (codons 1021-1035).

5

BP4 supporting: SpliceAI max delta 0.00 and Pangolin SG 0.003 / SL -0.007 show no splice impact, below the 0.1 benign threshold.

6

BP7 supporting: this synonymous variant is at/beyond +7/-21 and multiple algorithms predict no splice-site impact and no new site created.

Final determination: ClinGen InSiGHT APC v2.1 Rule26 is satisfied because the stand-alone benign criterion BA1 is met (gnomAD popmax filtering AF 0.85%/0.73% versus the 0.1% threshold), so the variant is classified Benign; the alternative Rule26 Condition1 with >=2 Benign.Strong criteria (BS1, BS2) independently yields Benign as well.

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.4893T>C is a synonymous change p.(Ser1631=) with SpliceAI max delta 0.00, so it is not an APC null variant.	cspec vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 vcep_apc_specifications_supplementary_material_v2 spliceai
PS1	Not met	Not met: the variant is synonymous p.(Ser1631=) with SpliceAI max delta 0.00, so it matches no established pathogenic missense change or splice-altering nucleotide.	cspec spliceai clinvar
PS2	Not assessed	Not assessed: no proband or parental testing evidence exists, so the VCEP's >=1 confirmed de novo score for PS2_Moderate cannot be derived.	cspec vcep_table_1_262 vcep_apc_specifications_supplementary_material_v2
PS3	Not assessed	Not assessed: no variant-specific RNA or protein functional assay exists for p.Ser1631=, so PS3 cannot be applied at any strength.	cspec clinvar oncokb
PS4	Not assessed	Not assessed: PS4 requires phenotype points >= 1 from an affected carrier, and no proband phenotype data exists for this variant.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 clinvar
PM1	N/A	Not applicable: the APC VCEP v2.1 specification retires PM1 for APC and the domain table holds no APC domain entry, so no hotspot or domain claim applies.	cspec vcep_apc_specifications_supplementary_material_v2
PM2	Not met	Not met: all-comers allele frequency 0.080% in gnomAD v2.1 exceeds the APC VCEP PM2 threshold of 0.0003%.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the APC VCEP Version 2.1 designates PM3 unused because FAP is autosomal dominant, not recessive.	cspec vcep_apc_specifications_supplementary_material_v2
PM4	N/A	Not applicable: the APC VCEP does not use PM4, and this synonymous substitution causes no protein-length change.	cspec vcep_apc_specifications_supplementary_material_v2
PM5	Not met	Not met: the variant is synonymous p.(Ser1631=) with no amino acid substitution, so the missense-residue PM5 rule yields zero comparator residues.	cspec pm5_candidates
PM6	Not assessed	Not assessed: no de novo observation is reported anywhere, so the VCEP's >=0.5 de novo score for even PM6_Supporting cannot be evaluated.	cspec vcep_table_1_262 vcep_apc_specifications_supplementary_material_v2
PP1	Not assessed	Not assessed: no family pedigrees or meioses are reported, so the VCEP's >=3 meioses required for PP1_Supporting cannot be evaluated.	cspec vcep_table_1_262
PP2	N/A	Not applicable: the APC VCEP v2.1 specification retires PP2 for APC, and the variant is synonymous p.(Ser1631=) rather than missense.	cspec vcep_apc_specifications_supplementary_material_v2
PP3	Not met	Not met: SpliceAI max delta 0.00 is below the 0.2 PP3 supporting threshold, so no deleterious splice effect is predicted.	cspec spliceai
PP4	N/A	Not applicable: the APC VCEP assigns PP4 to PS4 and states it cannot be used as independent evidence.	cspec vcep_apc_specifications_supplementary_material_v2
PP5	N/A	Not applicable: the APC VCEP does not use PP5, and no exact-variant ClinVar expert-panel Pathogenic classification exists.	cspec clinvar vcep_apc_specifications_supplementary_material_v2
BA1	Met	Met: gnomAD popmax filtering AF 0.85% (v4.1) and 0.73% (v2.1), well above the 0.1% APC VCEP stand-alone BA1 threshold.	cspec gnomad_v2 gnomad_v4
BS1	Met	Met: gnomAD popmax filtering AF 0.85%/0.73%, far above the APC VCEP BS1 threshold of 0.001%, though already subsumed by BA1.	cspec gnomad_v2 gnomad_v4
BS2	Met	Met: 9 homozygotes reported in gnomAD v4.1, exceeding the >=2 homozygous-state requirement of the APC VCEP BS2 Strong criterion.	cspec gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no RNA or beta-catenin activity assay of this synonymous p.Ser1631= variant exists; SpliceAI 0.00 is in-silico evidence only.	cspec clinvar oncokb
BS4	Not assessed	Not assessed: no affected relatives were tested, so the VCEP's >=0.5 phenotype points for BS4_Supporting cannot be evaluated.	cspec vcep_table_1_262
BP1	Met	Met at supporting: APC's disease mechanism is truncating variants, and this synonymous change at codon 1631 lies outside the VCEP's only BP1 exclusion (codons 1021-1035).	cspec PMID:25741868 PMID:26467025
BP2	Not assessed	Not assessed: no second APC variant and no cis/trans phase is documented, so neither the in-trans arm nor the 3-observation arm of the BP2 rule is satisfied.	cspec vcep_apc_specifications_supplementary_material_v2 clinvar gnomad_v2 gnomad_v4
BP3	N/A	Not applicable: the APC VCEP excludes BP3, and a synonymous SNV is not an in-frame indel in a repeat region.	cspec vcep_apc_specifications_supplementary_material_v2
BP4	Met	Met, supporting: synonymous c.4893T>C with SpliceAI max delta 0.00 and Pangolin near zero, both below the 0.1 BP4 threshold.	cspec spliceai
BP5	Not assessed	Not assessed: BP5 needs an alternate polyposis-gene (Likely) Pathogenic variant plus a polyposis phenotype, neither documented in this case.	cspec vcep_apc_specifications_supplementary_material_v2
BP6	N/A	Not applicable: the APC VCEP does not use BP6, and no exact-variant ClinVar expert-panel Benign classification exists.	cspec clinvar vcep_apc_specifications_supplementary_material_v2
BP7	Met	Met, supporting: this synonymous variant has SpliceAI max delta 0.00 and Pangolin near zero, concordantly predicting no splice-site impact.	cspec spliceai

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