Variant classification summary

NM_001127510.3:c.3374T>C

APC · NP_001120982.1:p.(Val1125Ala) · NM_001127510.3

GRCh37: chr5:112174665 T>C · GRCh38: chr5:112838968 T>C

Gene: APC Transcript: NM_001127510.3

Final call

Benign

BA1 stand-alone benign

Variant details

Gene

APC

Transcript

NM_001127510.3

Protein

NP_001120982.1:p.(Val1125Ala)

gnomAD AF

0.0001307323988341892 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BA1 (Stand-alone): East Asian popmax allele frequency 0.823% (gnomAD v2.1) and 0.379% (v4.1) exceeds the >=0.1% stand-alone benign threshold.

2

BS1 (Strong): formally met at >=0.001%, but it is the same population observation as BA1 and adds no independent evidence.

3

Benign overall: the InSiGHT APC VCEP v2.1 Rule 26 stand-alone rule terminates classification as Benign once BA1 is met.

Final determination: Rule26 of the ClinGen InSiGHT APC VCEP v2.1 criteria-combination framework is satisfied (1 Benign.Stand Alone criterion, BA1, met), therefore the variant NM_001127510.3:c.3374T>C (p.Val1125Ala) is classified as 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: PVS1 is limited to null variants, and this is a missense substitution (p.Val1125Ala) with no predicted splice impact (SpliceAI max delta 0.00).	cspec vcep_apc_specifications_supplementary_material_v2 vcep_fig_1_apc_pvs1_decision_tree_2023_10_20 spliceai
PS1	Not assessed	Not assessed: insufficient evidence was available to determine whether an established pathogenic variant produces the same amino-acid change.
PS2	Not assessed	Not assessed: insufficient evidence was available to confirm a de novo origin.
PS3	Not assessed	Not assessed: insufficient evidence was available from functional studies to judge impact on protein function.
PS4	Not met	Not met: no case-control enrichment - p.V1125A occurred in 3 of 80 Taiwanese CRC patients versus 1 of 74 controls, a non-significant difference.	cspec PMID:16569251 PMID:18199528 gnomad_v4 gnomad_v2
PM1	Not assessed	Not assessed: insufficient evidence was available to determine whether this position is a mutational hotspot or critical functional domain.
PM2	Not met	Not met: gnomAD v4.1 overall allele frequency 0.0131% is ~44-fold above the PM2 ceiling of <=0.0003%, so the variant is far from rare.	cspec gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PM4	N/A	Not applicable: APC VCEP v2.1 does not use PM4, and the criterion requires a protein-length change that a single missense substitution does not produce.	cspec vcep_apc_specifications_supplementary_material_v2
PM5	Not assessed	Not assessed: insufficient evidence was available to determine whether a different pathogenic missense change is known at this residue.
PM6	Not assessed	Not assessed: insufficient evidence was available to determine whether the variant arose de novo.
PP1	Not assessed	Not assessed: insufficient evidence was available to evaluate co-segregation with disease in affected relatives.
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
PP3	Not met	Not met: the APC VCEP permits only splicing predictions for missense variants, and SpliceAI reports max delta 0.00 - no predicted splicing impact.	cspec spliceai
PP4	N/A	Not applicable: the APC VCEP excludes PP4 because phenotype and family-history specificity is already captured under PS4.	cspec vcep_apc_specifications_supplementary_material_v2
PP5	N/A	Not applicable: the APC VCEP does not use PP5, and no ClinVar expert-panel pathogenic submission exists for c.3374T>C.	cspec vcep_apc_specifications_supplementary_material_v2 clinvar PMID:15604628 PMID:22138009 PMID:25356965 PMID:25373533
BA1	Met	Met (stand-alone): gnomAD East Asian popmax allele frequency 0.823% (v2.1) and 0.379% (v4.1) exceeds the >=0.1% BA1 threshold by 3- to 8-fold.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS1	Met	Met (strong): the same East Asian popmax frequencies (0.823% v2.1, 0.379% v4.1) exceed the >=0.001% BS1 threshold by several hundred-fold. Same observation as BA1, so not independent evidence.	cspec gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: roughly 0.5-1 healthy-individual point (one of 74 Taiwanese controls) and a single gnomAD homozygote fall short of the >=3 points or >=2 homozygotes required.	cspec gnomad_v2 PMID:16569251 PMID:18199528
BS3	Not assessed	Not assessed: insufficient evidence was available from functional studies to determine whether the variant lacks a damaging effect.
BS4	Not assessed	Not assessed: insufficient evidence was available to evaluate segregation among affected family members.
BP1	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
BP2	Not assessed	Not assessed: insufficient evidence was available to evaluate this criterion.
BP3	N/A	Not applicable: APC VCEP v2.1 excludes BP3, and the variant is a missense substitution rather than an in-frame indel in a repeat region.	cspec
BP4	N/A	Not applicable: the APC VCEP restricts BP4 to synonymous or intronic variants; c.3374T>C is a missense change.	cspec
BP5	Not met	Not met: no documented pathogenic variant in another polyposis gene (e.g., biallelic MUTYH or POLD1/POLE) was found in any p.Val1125Ala carrier.	cspec vcep_apc_specifications_supplementary_material_v2 PMID:16569251 PMID:18199528
BP6	N/A	Not applicable: the APC VCEP does not use BP6, and no ClinVar expert-panel benign submission exists for c.3374T>C.	cspec vcep_apc_specifications_supplementary_material_v2 clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants with no predicted splice impact; c.3374T>C is an exonic missense.	cspec

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