Variant classification summary

NM_001127510.3:c.608A>G

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

VUS

PM2 supporting BP1 supporting benign

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, a tumor suppressor gene where loss of function is the established disease mechanism for familial adenomatous polyposis.

2

The variant is absent from gnomAD v2.1, v4.1 (0/1,613,130 alleles), and gnomAD-Canada, meeting the APC VCEP PM2_Supporting criterion for rarity in population controls.

3

BP1 (supporting benign) is met: APC is a gene where primarily truncating variants cause disease, and this missense variant lies outside the excluded β-catenin binding domain region (codons 1021-1035). SpliceAI (max delta 0.01) shows no cryptic splice effect.

4

PVS1 is not met as this is a missense variant, not a null variant eligible under the APC VCEP decision tree.

5

No functional studies (PS3/BS3), de novo observations (PS2/PM6), segregation data (PP1/BS4), phenotype points (PS4), or pathogenic missense comparators at codon 203 (PM5) are available.

6

ClinVar reports this variant as Uncertain Significance (criteria provided, single submitter). No expert panel submission exists.

7

Per the APC VCEP Rules for Combining Criteria, a variant fulfilling only PM2_Supporting without any other pathogenic criterion remains a Variant of Uncertain Significance.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1 v2.1 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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 is a missense variant (p.Gln203Arg), not a null variant. PVS1 is restricted to null variants (nonsense, frameshift, canonical ±1,2 splice) per the APC VCEP decision tree (Figure 1). The variant does not fall into any PVS1-eligible bucket.	pvs1_gene_context pvs1_variant_assessment cspec
PS1	Not met	PS1 requires the same amino acid change as a previously established pathogenic or likely pathogenic variant. According to the APC VCEP, there are currently only two Likely Pathogenic missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). No missense variant has been classified as Pathogenic. The p.Gln203Arg change has not been previously classified as pathogenic or likely pathogenic.	cspec clinvar
PS2	Not met	No de novo observations have been reported for this variant. The APC VCEP PS2 criterion requires de novo scores (≥1 for moderate), but no de novo data for NM_001127510.3:c.608A>G were identified in the literature or ClinVar submissions.	cspec clinvar
PS3	Not met	No well-established in vitro or in vivo functional studies have been reported for NM_001127510.3:c.608A>G (p.Gln203Arg). The variant lies outside the β-catenin binding domain (codons 959-2129), so the VCEP protein assay pathway (β-catenin regulated transcription) does not apply. No RNA assay data are available for this missense variant. The literature search identified no variant-specific functional evidence.	cspec oncokb
PS4	Not met	No phenotype points can be assigned. The APC VCEP PS4 criterion requires quantification of affected individuals using phenotype points (≥1 point for supporting). No proband-specific clinical data with adenomatous polyposis phenotype were identified in the literature or ClinVar submissions for this variant. The ClinVar PMIDs are guideline/review papers, not case reports.	cspec clinvar
PS5	N/A	PS5 is not a recognized ACMG/AMP criterion code. The standard pathogenic criteria are PVS1, PS1-PS4, PM1-PM6, PP1-PP5. The equivalent criterion for reputable source reporting a variant as pathogenic is PP5, which the APC VCEP explicitly marks as Not Applicable.	cspec
PM1	N/A	The APC VCEP has determined that PM1 is not applicable for APC. The supplementary material states: 'Based on our knowledge there are no mutational hotspots or critical functional domains in APC.' Cancerhotspots.org also reports this residue is not a statistically significant hotspot.	cspec
PM2	Met	This variant is absent from gnomAD v2.1, gnomAD v4.1 (0/1,613,130 alleles), and gnomAD-Canada. Per the APC VCEP, PM2_Supporting applies when allele frequency is below the defined threshold: AF ≤ 0.0003% if AC > 1, or AF < 0.001% if AC ≤ 1. The variant meets this criterion as it is entirely absent from population databases.	gnomad_v2 gnomad_v4 gnomad_canada cspec
PM5	Not met	PM5 requires a different pathogenic or likely pathogenic missense change at the same amino acid residue. The APC VCEP recognizes only two LP missense variants: c.3077A>G p.(Asn1026Ser) and c.3084T>A p.(Ser1028Arg). No pathogenic or likely pathogenic missense variant has been reported at codon 203 (Gln203). The ClinVar classification for this variant itself is VUS.	cspec pm5_candidates clinvar
PM6	Not met	No assumed de novo observations have been reported. The APC VCEP PM6 criterion requires de novo scores (≥0.5 for supporting), but no de novo data were identified in the literature or ClinVar submissions.	cspec clinvar
PP1	Not met	No co-segregation data have been reported for this variant. The APC VCEP PP1 criterion requires segregation in 3-4 meioses for supporting strength. No segregation studies were identified in the literature.	cspec
PP2	N/A	The APC VCEP marks PP2 as Not Applicable. Missense variants are not a frequent mechanism of disease in APC, which is primarily a truncating-variant disease gene.	cspec
PP3	Not met	The APC VCEP states that for missense variants, computational prediction models for conservation and evolution should not be used. Only in silico splicing predictors may be applied. SpliceAI predicts no significant splice impact (max delta score = 0.01). REVEL (0.426) and BayesDel (0.206) are not used per VCEP guidance for missense variants. No multiple lines of splicing evidence support a deleterious effect.	cspec spliceai revel bayesdel
PP4	N/A	The APC VCEP marks PP4 as Not Applicable. The supplementary material states that PP4 is already captured by the specifications of PS4, and is therefore not used independently.	cspec
PP5	N/A	The APC VCEP marks PP5 as Not Applicable, following the recommendation of Biesecker et al. 2018. Additionally, this variant is classified as Uncertain Significance in ClinVar (criteria provided, single submitter), not as pathogenic.	cspec clinvar
BA1	Not met	The APC VCEP BA1 threshold is a gnomAD Popmax Filtering Allele Frequency ≥ 0.1% (0.001). This variant is absent from gnomAD v2.1, v4.1 (0/1,613,130 alleles), and gnomAD-Canada. The allele frequency of 0.0 does not meet the BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada cspec
BS1	Not met	The APC VCEP BS1 threshold is a gnomAD Popmax Filtering Allele Frequency ≥ 0.001% (0.00001). This variant is absent from gnomAD v2.1 and v4.1. The allele frequency of 0.0 does not meet the BS1 threshold.	gnomad_v2 gnomad_v4 cspec
BS2	Not met	No healthy adult individuals carrying this variant have been reported. The APC VCEP BS2 requires ≥3 points for healthy individuals (supporting) or ≥10 points (strong), with points defined by age ≥50, <5 adenomatous polyps, and absence of FAP features. No such data are available for this variant.	cspec
BS3	Not met	No well-established functional studies show no damaging effect. The APC VCEP BS3 requires RNA assays demonstrating no mRNA aberration (for synonymous/intronic variants) or protein assays showing retention of β-catenin regulated transcription (for variants within codons 959-2129). This missense variant at codon 203 is outside the β-catenin binding domain, and no functional studies have been reported.	cspec
BS4	Not met	No data on lack of segregation in affected family members. The APC VCEP BS4 requires affected members without the variant scoring phenotype points. No segregation or family studies were identified for this variant.	cspec
BP1	Met	BP1 applies to missense variants in APC, a gene for which primarily truncating variants are known to cause disease. The APC VCEP states BP1 is applicable with the exception of missense variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035). This variant (p.Gln203Arg) is at codon 203, well outside that excluded region. SpliceAI confirms no cryptic splicing (max delta 0.01).	cspec spliceai
BP2	Not met	No evidence of this variant observed in trans with a (likely) pathogenic APC variant, nor observed ≥3 times in unknown phase with different (likely) pathogenic APC variants. The APC VCEP BP2 criterion requires such observations.	cspec
BP4	N/A	The APC VCEP explicitly states that BP4 is not applicable for missense variants. The supplementary material notes: 'BP4 is not applicable for missense variants according to the APC VCEP.'	cspec
BP5	Not met	BP5 requires an alternate genetic basis for the colorectal polyposis phenotype (e.g., a pathogenic variant in POLD1, POLE, MUTYH, NTHL1, MSH3, or mismatch repair genes). No such alternate molecular diagnosis has been reported in any individual carrying this variant.	cspec
BP6	N/A	The APC VCEP marks BP6 as Not Applicable for this VCEP, as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.	cspec
BP7	N/A	BP7 is applicable only to synonymous (silent) or intronic variants at or beyond +7/-21 for which multiple splicing prediction algorithms predict no impact. NM_001127510.3:c.608A>G is a missense variant (p.Gln203Arg), not synonymous or intronic.	cspec

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