Variant classification summary

NM_001127510.3:c.2805C>T

APC · NP_001120982.1:p.(Tyr935=) · NM_001127510.3

GRCh37: chr5:112174096 C>T · GRCh38: chr5:112838399 C>T

Gene: APC Transcript: NM_001127510.3

Final call

Likely Benign

BS1 strong BP4 supporting BP7 supporting

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(Tyr935=)

gnomAD AF

0.0005067575939298122 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1 (Strong): gnomAD non-cancer Popmax allele frequency 0.0686% exceeds the 0.001% BS1 threshold.

2

BP4 (Supporting): two in silico predictors (SpliceAI max delta 0.00) find no splicing impact from this synonymous variant.

3

BP7 (Supporting): SpliceAI and Pangolin predict no splice-site impact for this deep-exonic synonymous change.

4

Likely Benign overall: one strong benign criterion (BS1) and two benign supporting criteria (BP4 and BP7) each independently satisfy the APC expert-panel benign rules.

Final determination: Under the InSiGHT APC VCEP v2.1 criteria-combination framework, BS1 alone (exactly one benign strong criterion) and BP4+BP7 (at least two benign supporting criteria, Rule19) each independently combine to Likely Benign; no rule combination reaches Benign or VUS is satisfied, so the final call is Likely 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	N/A	Not applicable: c.2805C>T is a synonymous substitution (p.Tyr935=), not a null variant, with no predicted splicing effect (SpliceAI max delta 0.00).	cspec PMID:25741868
PS1	N/A	Not applicable: PS1 requires a missense change or splicing effect at the same nucleotide; this synonymous polymorphism (p.Tyr935=) is neither.	cspec PMID:12173026
PS2	Not assessed	Not assessed: no case evidence shows this variant arose de novo; parental genotypes and maternity/paternity confirmation are absent.	cspec PMID:12173026
PS3	Not assessed	Not assessed: no RNA or protein functional assay results were available to test for a pathogenic transcript or protein effect.	cspec PMID:12173026
PS4	Not assessed	Not assessed: no proband counts, phenotype-point data, or case-control enrichment analysis were available for this variant.	cspec vcep_apc_specifications_supplementary_material_v2 vcep_table_1_262 PMID:12173026
PM1	N/A	Not applicable: the APC expert panel does not use PM1, and this synonymous change is not a missense variant in a functional hotspot.	cspec
PM2	Not met	Not met: gnomAD allele frequency 0.000457 (allele count 129) far exceeds the PM2 supporting threshold of <=0.000003.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: the APC expert panel does not use PM3; APC-associated polyposis follows autosomal dominant inheritance.	cspec
PM4	N/A	Not applicable: the APC expert panel does not use PM4, and this synonymous change leaves protein length unaltered.	cspec PMID:25741868
PM5	N/A	Not applicable: PM5 applies only to missense changes at established pathogenic residues; this variant is synonymous (p.Tyr935=).	cspec pm5_candidates
PM6	Not assessed	Not assessed: no case evidence supports an assumed de novo occurrence; inheritance and parental testing are undocumented.	cspec PMID:12173026
PP1	Not assessed	Not assessed: no family segregation data exist for this variant; no affected relatives or informative meioses were documented.	cspec PMID:12173026
PP2	N/A	Not applicable: the APC expert panel does not use PP2; the gene-specific specification takes precedence.	cspec
PP3	Not met	Not met: this synonymous variant shows no predicted splice impact, whereas PP3 requires multiple in silico predictors supporting a deleterious splicing effect.	cspec spliceai
PP4	N/A	Not applicable: the APC expert panel captures phenotype evidence under its PS4 framework rather than PP4.	cspec vcep_apc_specifications_supplementary_material_v2
PP5	N/A	Not applicable: not used by the APC expert panel, and ClinVar has no expert-panel pathogenic assertion for this variant.	cspec vcep_apc_specifications_supplementary_material_v2 clinvar
BA1	Not met	Not met: gnomAD non-cancer Popmax allele frequency 0.000686 (0.069%) is below the 0.1% BA1 threshold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Met	Met at Strong: gnomAD v2.1 non-cancer Popmax allele frequency 0.000686 (0.069%) exceeds the 0.001% BS1 threshold.	cspec gnomad_v2
BS2	Not met	Not met: gnomAD reports zero homozygotes, and no healthy individuals with the required phenotype details were documented.	cspec gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no RNA or protein functional assay in a patient sample was available to demonstrate normal function.	cspec PMID:12173026
BS4	Not assessed	Not assessed: no affected family member without this variant was documented, so lack of segregation cannot be shown.	cspec PMID:12173026
BP1	N/A	Not applicable: BP1 addresses missense variants; this is a synonymous substitution (p.Tyr935=).	cspec PMID:12173026
BP2	Not assessed	Not assessed: no second pathogenic APC variant in trans, or repeated unknown-phase observations, was documented.	cspec PMID:12173026
BP3	N/A	Not applicable: the APC expert panel does not use BP3, and this is a synonymous substitution, not an in-frame indel.	cspec PMID:25741868
BP4	Met	Met at Supporting: two in silico predictors found no splicing impact (SpliceAI max delta 0.00) for this synonymous variant.	cspec spliceai
BP5	Not assessed	Not assessed: no evidence documents an alternate genetic basis explaining the polyposis phenotype.	cspec vcep_apc_specifications_supplementary_material_v2
BP6	N/A	Not applicable: not used by the APC expert panel, and no expert-panel ClinVar submissions exist for this variant.	cspec clinvar
BP7	Met	Met at Supporting: SpliceAI and Pangolin predict no splice-site impact, consistent with a benign synonymous variant.	cspec spliceai

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