Variant classification summary

NM_001127510.3:c.4237A>G

APC · NP_001120982.1:p.(Met1413Val) · NM_001127510.3

GRCh37: chr5:112175528 A>G · GRCh38: chr5:112839831 A>G

Gene: APC Transcript: NM_001127510.3

Final call

Likely Benign

BS1 strong BP1 supporting

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(Met1413Val)

gnomAD AF

0.00021683668728060773 (v4.1)

ClinVar

Likely benign

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Benign: BS1 strong is met because gnomAD v4.1 Popmax filtering AF 0.00023147 exceeds the APC VCEP threshold of 0.00001.

2

Likely Benign: BP1 supporting is met because codon 1413 lies outside the APC VCEP exception covering codons 1021-1035.

Final determination: APC VCEP Version 2.1 Rule26 is satisfied by one Benign.Strong criterion, so the final classification 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	Not met	Not met: c.4237A>G is a missense variant causing p.Met1413Val, not an APC null variant eligible for the VCEP PVS1 decision tree.	cspec PMID:20233475
PS1	Not met	Not met: p.Met1413Val is not one of the APC VCEP's two established likely pathogenic missense comparators, p.Asn1026Ser or p.Ser1028Arg.	cspec PMID:18199528 PMID:20233475
PS2	Not assessed	Not assessed: no documented confirmed maternity-and-paternity testing or validated de novo observation is available for the proband.	cspec
PS3	Not assessed	Not assessed: no variant-specific functional assay demonstrates that APC p.(Met1413Val) damages protein function or splicing under the APC VCEP criteria.	cspec PMID:18199528 PMID:20233475 PMID:21859464 PMID:23085758
PS4	Not met	Not met: M1413V occurred in one polyposis patient and three healthy controls, without a qualifying phenotype-point total or case-control enrichment estimate.	cspec vcep_table_1_262 PMID:18199528 PMID:20233475
PM1	N/A	Not applicable: the APC VCEP explicitly marks PM1 as not applicable, and no APC domain-table entry is supplied for residue 1413.	cspec
PM2	Not met	Not met: gnomAD v4.1 AF 0.000216837 from 350/1,614,118 alleles exceeds the APC VCEP PM2 threshold of 0.000003 for allele count above one.	cspec gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: APC familial adenomatous polyposis is autosomal dominant, so the VCEP excludes recessive PM3 evidence.	cspec
PM4	N/A	Not applicable: the APC VCEP explicitly excludes PM4, and p.Met1413Val causes no protein-length change.	cspec
PM5	Not assessed	Not assessed: no qualifying alternate missense comparator at residue 1413 was identified, and same-residue retrieval ended with an HTTP 429 rate-limit error.	cspec pm5_candidates PMID:18199528 PMID:20233475
PM6	Not assessed	Not assessed: the evidence does not report an apparently de novo proband or parental testing sufficient to assign any PM6 de novo score.	cspec
PP1	Not assessed	Not assessed: the reports provide no qualifying count of affected meioses, while M1413V was also observed in unaffected relatives and healthy controls.	cspec PMID:20233475 PMID:18199528
PP2	N/A	Not applicable: the APC VCEP explicitly excludes PP2 because missense variants are not a frequent APC disease mechanism.	cspec
PP3	Not met	Not met: REVEL 0.587 is below the >=0.644 supporting PP3 threshold for missense variants.	cspec revel
PP4	N/A	Not applicable: the APC VCEP explicitly excludes PP4 because phenotype specificity is captured by its PS4 phenotype-point system.	cspec
PP5	N/A	Not applicable: the APC VCEP excludes PP5, and ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 Popmax filtering AF 0.00023147 is below the APC VCEP BA1 threshold of 0.001.	cspec gnomad_v4 gnomad_v2
BS1	Met	Met, strong: gnomAD v4.1 Popmax filtering AF 0.00023147 exceeds the APC VCEP BS1 threshold of 0.00001.	cspec gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD reports 0 homozygotes, while three healthy-control observations provide only 1.5 APC VCEP points versus the 3-point BS2 Supporting threshold.	cspec gnomad_v4 gnomad_v2 PMID:18199528 PMID:20233475
BS3	Not assessed	Not assessed: no variant-specific assay shows APC p.(Met1413Val) retains wild-type function or normal RNA processing under the APC VCEP criteria.	cspec PMID:18199528 PMID:20233475 PMID:21859464 PMID:23085758
BS4	Not assessed	Not assessed: unaffected carriers and healthy controls are reported, but no affected noncarrier meeting the APC phenotype-point threshold is documented.	cspec PMID:20233475 PMID:18199528
BP1	Met	Met, supporting: codon 1413 lies outside the APC VCEP BP1 exception covering only the first repeat at codons 1021-1035.	cspec
BP2	Not assessed	Not assessed: one patient had M1413V plus a premature-termination APC variant, but phase was not established and the VCEP requires trans or at least three unknown-phase observations.	cspec PMID:20233475
BP3	N/A	Not applicable: the APC VCEP explicitly excludes BP3, and p.Met1413Val is not an in-frame repeat-region insertion or deletion.	cspec
BP4	N/A	Not applicable: the APC VCEP expressly excludes missense variants from BP4, regardless of predictor scores.	cspec
BP5	Not met	Not met: no (Likely) Pathogenic variant in another adenomatous polyposis gene is documented, and the reported second variant was also in APC.	cspec PMID:20233475
BP6	N/A	Not applicable: the APC VCEP excludes BP6, and ClinVar has no exact-variant expert-panel Benign or Likely benign classification.	cspec clinvar
BP7	N/A	Not applicable: BP7 is restricted to synonymous variants, whereas this variant is missense p.(Met1413Val).	cspec

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.