LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
APC
· NP_001120982.1:p.(Gln203Arg)
· NM_001127510.3
GRCh37: chr5:112116563 A>G
·
GRCh38: chr5:112780866 A>G
Gene:
APC
Transcript:
NM_001127510.3
Final call
Variant details
Gene
APC
Transcript
NM_001127510.3
Protein
NP_001120982.1:p.(Gln203Arg)
gnomAD AF
0.0 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
NM_001127510.3:c.608A>G (p.Gln203Arg) is a missense variant in APC exon 7. It is absent from gnomAD population databases (PM2_Supporting per APC VCEP).
2
As a missense variant in APC, a gene where primarily truncating variants cause disease, BP1 is met at supporting benign strength. The variant lies at codon 203, outside the excluded β-catenin binding domain region (codons 1021-1035).
3
No variant-specific functional data, de novo observations, co-segregation data, or case-control data are available. SpliceAI predicts no splicing impact (max delta 0.01). The variant is classified as Uncertain Significance in ClinVar (7 submissions, criteria provided single submitter).
4
With one pathogenic supporting criterion (PM2_Supporting) and one benign supporting criterion (BP1), the evidence is balanced, consistent with a classification of Uncertain Significance per the APC VCEP rules for combining criteria.
Final determination:
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 | NM_001127510.3:c.608A>G (p.Gln203Arg) is a missense variant, not a null variant. PVS1 under the APC VCEP applies only to null variants (nonsense, frameshift, canonical splice sites) per the modified decision tree (Figure 1). This variant does not fall into any PVS1-eligible bucket. |
pvs1_gene_context
pvs1_variant_assessment
vcep_fig_1_apc_pvs1_decision_tree_2023_10_20
|
| PS1 | Not met | This variant results in p.Gln203Arg. No previously established pathogenic or likely pathogenic variant results in the same amino acid change at this position. The only two likely pathogenic missense variants acknowledged by the APC VCEP are p.Asn1026Ser (c.3077A>G) and p.Ser1028Arg (c.3084T>A), which are unrelated to Gln203Arg. |
cspec
|
| PS2 | Not met | No de novo observation data are available for this variant in the case materials. PS2 requires at least 1 de novo score per the APC VCEP Table 1/Table 2 scoring system. |
|
| PS3 | Not met | No functional studies testing NM_001127510.3:c.608A>G were identified. The APC VCEP PS3 rules are RNA-based (premature stop codon, exon skipping) and are not applicable to this missense variant without splicing impact (SpliceAI max delta 0.01). No variant-specific protein functional data were found. |
spliceai
oncokb
|
| PS4 | Not met | No phenotype-scored probands with this variant are available in the case materials. PS4 requires phenotype points per the APC VCEP Table 1; no proband clinical data were provided. |
|
| PS5 | Not assessed | PS5 is not part of the standard ACMG/AMP 2015 framework and was not listed in the VCEP criteria. Not assessed per adjudication scope. |
|
| PM1 | N/A | PM1 is marked as not applicable in the APC VCEP specifications. Per the supplementary material: 'Based on our knowledge there are no mutational hotspots or critical well-established functional domains without benign variation in APC.' |
cspec
|
| PM2 | Met | This variant is absent from gnomAD v2.1 and v4.1 (0/1,613,130 alleles). Per the APC VCEP PM2 rule, allele frequency <0.001% (0.00001) qualifies for PM2_Supporting when allele count is ≤1. |
gnomad_v2
gnomad_v4
cspec
|
| PM5 | Not met | This variant causes p.Gln203Arg. No other missense variant at codon 203 has been classified as pathogenic or likely pathogenic. The APC VCEP recognizes only p.Asn1026Ser and p.Ser1028Arg as LP missense variants; these are at unrelated residues. |
pm5_candidates
cspec
|
| PM6 | Not met | No de novo observations (assumed or confirmed) are available for this variant. PM6 requires at least 0.5 de novo scores per the APC VCEP Table 1/Table 2. |
|
| PP1 | Not met | No co-segregation data are available. PP1 requires variant segregation in at least 3 meioses in 1 family per the APC VCEP. |
|
| PP2 | N/A | PP2 is marked as not applicable in the APC VCEP. Per the supplementary material: 'Missense variants are not a frequent mechanism of disease in APC; primarily truncating variants cause disease.' |
cspec
|
| PP3 | Not met | Per the APC VCEP, for missense variants, computational prediction models for conservation and evolution must not be used; only in silico splicing predictors may be considered. SpliceAI predicts no significant splice impact (max delta score 0.01). No evidence of a splicing defect. |
spliceai
cspec
|
| PP4 | N/A | PP4 is marked as not applicable in the APC VCEP. Per the supplementary material: 'Already captured by the specifications of PS4, and therefore not used independently.' |
cspec
|
| PP5 | N/A | PP5 is marked as not applicable for the APC VCEP per ClinGen SVI VCEP Review Committee recommendations. ClinVar classification for this variant is Uncertain Significance (criteria provided, single submitter), not a 3-star expert panel classification, so the PP5 override does not apply. |
cspec
clinvar
|
| BA1 | Not met | This variant is absent from gnomAD. The APC VCEP BA1 threshold is gnomAD popmax filtering allele frequency ≥0.1% (0.001). Observed frequency of 0 does not meet this threshold. |
gnomad_v2
gnomad_v4
cspec
|
| BS1 | Not met | This variant is absent from gnomAD. The APC VCEP BS1 threshold is gnomAD popmax filtering allele frequency ≥0.001% (0.00001). Observed frequency of 0 does not meet this threshold. |
gnomad_v2
gnomad_v4
cspec
|
| BS2 | Not met | No healthy adult individuals carrying this variant were identified in the case materials. BS2 requires ≥3 healthy individual points per the APC VCEP scoring system. No homozygous observations in gnomAD either. |
|
| BS3 | Not met | No functional studies showing no damaging effect were identified for this variant. The APC VCEP BS3 rules apply to RNA assays (synonymous/intronic variants) or protein assays within the β-catenin binding domain (codons 959-2129). This variant is at codon 203, outside the β-catenin binding domain for BS3_protein, and is a missense variant without splicing impact. |
spliceai
cspec
|
| BS4 | Not met | No family segregation data are available to demonstrate lack of segregation in affected members. BS4 requires affected members without the variant scoring phenotype points per APC VCEP Table 1. |
|
| BP1 | Met | This is a missense variant in APC, a gene where primarily truncating variants cause disease. The APC VCEP states BP1 is applicable to APC with the exception of missense variants in the first 15-amino acid repeat of the β-catenin binding domain (codons 1021-1035). This variant at codon 203 is not in the exclusion range. |
cspec
|
| BP2 | Not met | No observation of this variant in trans with a (likely) pathogenic APC variant, and no observations in unknown phase with different (likely) pathogenic APC variants. |
|
| BP4 | N/A | Per the APC VCEP, BP4 is not applicable for missense variants. BP4 applies only to synonymous (silent) or intronic variants where multiple in silico splicing predictors suggest no impact. |
cspec
|
| BP5 | Not met | No alternate genetic basis for the colorectal polyposis phenotype has been identified in this case. The APC VCEP BP5 applies when a (likely) pathogenic variant is found in another adenomatous polyposis gene. |
|
| BP6 | N/A | BP6 is marked as not applicable for the APC VCEP per ClinGen SVI VCEP Review Committee recommendations. ClinVar classification for this variant is Uncertain Significance (criteria provided, single submitter), not a 3-star expert panel benign classification, so the BP6 override does not apply. |
cspec
clinvar
|
| BP7 | N/A | BP7 is applicable only to synonymous (silent) or intronic variants. NM_001127510.3:c.608A>G is a missense variant (p.Gln203Arg). |
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.