Variant classification summary

NM_001127510.3:c.6196A>G

APC · NP_001120982.1:p.(Arg2066Gly) · NM_001127510.3

GRCh37: chr5:112177487 A>G · GRCh38: chr5:112841790 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.(Arg2066Gly)

gnomAD AF

2.3544223486726016e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1 strong: gnomAD v4.1 Popmax Filtering AF 2.314e-05 exceeds the APC VCEP threshold of 1e-05.

2

BP1 supporting: codon 2066 lies outside the APC VCEP exception limited to codons 1021-1035.

Final determination: Under Rule26 of the ClinGen InSiGHT APC Version 2.1 framework, one Benign.Strong criterion is sufficient for a Likely Benign classification; BS1 strong satisfies this rule, with BP1 supporting also applied.

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: NM_001127510.3:c.6196A>G is a missense variant encoding p.(Arg2066Gly), not a null variant eligible for PVS1.	cspec vcep_fig_1_apc_pvs1_decision_tree_2023_10_20
PS1	Not met	Not met: p.Arg2066Gly matches neither of the APC VCEP's two established likely pathogenic missense changes, p.Asn1026Ser or p.Ser1028Arg.	cspec
PS2	Not assessed	Not assessed: no de novo score, parental genotypes, or confirmed maternity and paternity are documented for APC c.6196A>G.	cspec vcep_table_1_262 PMID:18199528
PS3	Not assessed	Not assessed: the exact-variant report tested other APC variants, with no validated damaging assay result reported for p.Arg2066Gly.	cspec PMID:18199528
PS4	Not assessed	Not assessed: APC R2066G was reported in one patient, but the adenoma count needed for the VCEP phenotype-point thresholds is unspecified.	cspec vcep_table_1_262 PMID:18199528
PM1	N/A	Not applicable: the APC VCEP version 2.1 explicitly designates PM1 as not applicable, and no authoritative APC domain table is supplied.	cspec vcep_apc_specifications_supplementary_material_v2
PM2	Not met	Not met: gnomAD v4.1 AF 2.35442e-05 with AC 38 exceeds the APC VCEP PM2 threshold of 3e-06 for AC greater than 1.	cspec gnomad_v4 gnomad_v2
PM3	N/A	Not applicable: APC familial adenomatous polyposis is autosomal dominant, and the APC VCEP explicitly designates PM3 as not applicable.	cspec
PM4	N/A	Not applicable: the APC VCEP does not use PM4, and this variant changes one amino acid without altering protein length.	cspec vcep_apc_specifications_supplementary_material_v2
PM5	Not met	Not met: no pathogenic or likely pathogenic alternate missense variant at APC residue Arg2066 was identified for comparison with p.Arg2066Gly.	cspec pm5_candidates PMID:18199528
PM6	Not assessed	Not assessed: the only variant-specific report describes R2066G as inherited but provides no parental results or VCEP de novo score.	cspec vcep_table_1_262 PMID:18199528
PP1	Not assessed	Not assessed: no informative meioses, affected relatives, or family-level segregation data are reported for APC c.6196A>G.	cspec PMID:18199528
PP2	N/A	Not applicable: the APC VCEP version 2.1 designates PP2 as not applicable for APC missense variants.	cspec vcep_apc_specifications_supplementary_material_v2
PP3	Not assessed	Not assessed: SpliceAI returned no score, while REVEL 0.572 is below the generic PP3 supporting threshold of 0.644.	cspec spliceai revel bayesdel
PP4	N/A	Not applicable: the APC VCEP directs that phenotype specificity be captured through PS4 rather than independent PP4 use.	cspec vcep_apc_specifications_supplementary_material_v2
PP5	N/A	Not applicable: 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 2.314e-05 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 2.314e-05 exceeds the APC VCEP BS1 threshold of 1e-05.	cspec gnomad_v4
BS2	Not assessed	Not assessed: gnomAD v4.1 reports 0 homozygotes, but no qualifying healthy-individual data are available to evaluate the alternative 10-point BS2 branch.	cspec gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no exact-variant assay showed wild-type-like APC function or normal splicing for p.Arg2066Gly under the VCEP BS3 requirements.	cspec PMID:18199528
BS4	Not assessed	Not assessed: no affected non-carrier relative or phenotype-point score is documented for APC c.6196A>G.	cspec vcep_table_1_262
BP1	Met	Met at supporting: APC codon 2066 is outside the VCEP BP1 exception limited to the first beta-catenin-binding repeat, codons 1021-1035.	cspec
BP2	Not met	Not met: R2066G was reported in one patient, but no pathogenic APC partner or cis/trans phase was documented, so the VCEP threshold was not satisfied.	cspec PMID:18199528
BP3	N/A	Not applicable: the APC VCEP explicitly marks BP3 as not applicable, and c.6196A>G is not an in-frame indel in a repeat region.	cspec vcep_apc_specifications_supplementary_material_v2
BP4	N/A	Not applicable: APC VCEP excludes missense variants from BP4, which is limited to synonymous or intronic splice-impact assessment.	cspec
BP5	Not assessed	Not assessed: multiple colorectal adenomas are reported, but no pathogenic alternate-gene result is documented to satisfy the APC BP5 rule.	cspec PMID:18199528
BP6	N/A	Not applicable: 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 or intronic variants, whereas this variant causes the missense change p.(Arg2066Gly).	cspec

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