Variant classification summary

NM_001127510.3:c.8511T>C

APC · NP_001120982.1:p.(Ser2837=) · NM_001127510.3

GRCh37: chr5:112179802 T>C · GRCh38: chr5:112844105 T>C

Gene: APC Transcript: NM_001127510.3

Final call

Likely Benign

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(Ser2837=)

gnomAD AF

3.0998831964011597e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v2.1, the APC panel's designated population dataset.

2

BP4 (Supporting): SpliceAI max delta 0.00 predicts no splice impact, indicating no effect on gene or gene product.

3

BP7 (Supporting): synonymous change with SpliceAI max delta 0.00 predicts no splice-consensus disruption or new splice site.

4

Three supporting benign criteria (PM2 + BP4 + BP7) satisfy APC VCEP Rule 19's benign combination while no pathogenic rule is met, yielding Likely Benign.

Final determination: Rule19 (Benign.Supporting, >=2 of BS2_Supporting/BS3_Supporting/BS4_Supporting/BP1/BP2/BP4/BP5/BP7) satisfied by BP4+BP7 -> 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: this synonymous change produces no amino acid alteration, so it is not a loss-of-function null variant.	cspec spliceai
PS1	N/A	Not applicable: no amino acid change or splicing effect exists to match against a previously established pathogenic variant.	cspec
PS2	Not assessed	Not assessed: no de novo occurrence in an affected proband with confirmed parentage is documented.	cspec
PS3	Not assessed	Not assessed: no RNA or protein functional assay of this variant was available.
PS4	Not assessed	Not assessed: no affected-proband observations or case-control enrichment data were available.	cspec
PM1	N/A	Not applicable: the APC expert panel designates no hotspot or critical-domain rule for this gene.	cspec
PM2	Met	Met (Supporting): absent from gnomAD v2.1, the APC panel's designated population dataset.	cspec gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: familial adenomatous polyposis is autosomal dominant, so the recessive PM3 rule does not apply.	cspec vcep_apc_specifications_supplementary_material_v2
PM4	N/A	Not applicable: the synonymous change leaves protein length and sequence unchanged.	cspec
PM5	N/A	Not applicable: PM5 applies only to missense variants, and this change is synonymous.	cspec
PM6	Not assessed	Not assessed: no presumed de novo occurrence with unconfirmed parental relationships is documented.	cspec
PP1	Not assessed	Not assessed: no family segregation data were available for this variant.	cspec
PP2	N/A	Not applicable: the APC expert panel marks the missense-constraint rule PP2 as not applicable for this gene.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.00 predicts no splice impact, below the threshold for a deleterious-splicing call.	cspec spliceai
PP4	N/A	Not applicable: phenotype evidence is captured under the APC-specific PS4 rule.	cspec
PP5	N/A	Not applicable: no expert-panel ClinVar submission exists for this variant to support a benign assertion.	cspec clinvar
BA1	Not met	Not met: gnomAD filtering allele frequency 7.9e-07 (0.000079%) versus the required >=0.1% threshold.	cspec gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD filtering allele frequency 7.9e-07 (0.000079%) versus the required >=0.001% threshold.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy-individual observations or homozygotes were available.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no RNA assay demonstrating normal splicing of this variant was available.
BS4	Not assessed	Not assessed: no informative non-segregation evidence was available.	cspec
BP1	N/A	Not applicable: BP1 applies to missense variants, not this synonymous change.	cspec
BP2	Not assessed	Not assessed: no co-occurrence data with a pathogenic APC variant were available.	cspec vcep_apc_specifications_supplementary_material_v2
BP3	N/A	Not applicable: BP3 requires an in-frame insertion or deletion, and this is a single-nucleotide synonymous substitution.	cspec
BP4	Met	Met (Supporting): SpliceAI max delta 0.00 predicts no splice impact, indicating no effect on gene or gene product.	cspec spliceai
BP5	Not assessed	Not assessed: no evidence established an alternate genetic basis for the phenotype.	cspec
BP6	N/A	Not applicable: no expert-panel benign ClinVar classification exists for this variant.	cspec clinvar
BP7	Met	Met (Supporting): synonymous change with SpliceAI max delta 0.00 predicts no splice-consensus disruption or new splice site.	cspec spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.