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NM_001127510.3:c.6196A>G
p.Arg2066Gly · APC
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for APC Version 2.1 · v2.1
0%
complete
Final classification
Likely Benign
BS1BP1
APC
c.6196A>G
p.Arg2066Gly
missense · exon 17
Gene context NCBI Gene ↗ OncoKB ↗

APC is a tumor suppressor gene whose protein acts as a key brake on the Wnt signaling pathway by helping mark the growth-promoting protein beta-catenin for destruction; it also participates in cell migration, adhesion, and apoptosis. Inherited mutations in APC cause familial adenomatous polyposis (FAP), an autosomal dominant condition characterized by numerous colorectal polyps and a very high risk of colorectal cancer, with related forms including attenuated FAP and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). Somatic APC mutations are found in roughly 50-80% of sporadic colorectal cancers, where they act as early tumor-initiating events, and are also observed in some breast, stomach, and prostate cancers. Loss of APC function leaves Wnt signaling abnormally active, driving uncontrolled cell growth, which makes APC a central tumor suppressor in colorectal cancer.

This variant

As an APC missense variant, NM_001127510.3:c.6196A>G affects a tumor-suppressor gene whose loss of function abnormally activates Wnt signaling and contributes to inherited colorectal polyposis and colorectal cancer risk.

Transcript
NM_001127510.3
HGVS · transcript:coding
NM_001127510.3:c.6196A>G
GRCh38
chr5:112841790 A>G
GRCh37
chr5:112177487 A>G
Likely Benign: BS1 strong plus BP1 supporting satisfy Rule26 of the APC InSiGHT VCEP Version 2.1 framework.
Classification rationale
BS1BP1 Likely Benign
APC c.6196A>G missense · exon 17

BS1 strong: gnomAD v4.1 Popmax Filtering AF 2.314e-05 exceeds the APC VCEP threshold of 1e-05. BP1 supporting: codon 2066 lies outside the APC VCEP exception limited to codons 1021-1035.

BS1 + BP1 → Likely Benign
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
Gene diagram · NM_001127510.3 · variants mapped to exon structure
APC NM_001127510.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 2
Strength Supporting Moderate Strong Very strong
BS1 strong Benign
Met, strong: gnomAD v4.1 Popmax Filtering AF 2.314e-05 exceeds the APC VCEP BS1 threshold of 1e-05.
The APC VCEP specifies BS1 at gnomAD Popmax Filtering AF >= 0.001% (0.00001), at strong strength.gnomAD v4.1 reports grpmax FAF 2.314e-05 and highest observed subpopulation AF 3.135704830171922e-05, both above 1e-05.The APC specification does not identify a required non-cancer or exome-only population source, so the all-comers gnomAD v4.1 entry is the applicable default.
cspec ↗gnomad_v4 ↗
BP1 supporting Benign
Met at supporting: APC codon 2066 is outside the VCEP BP1 exception limited to the first beta-catenin-binding repeat, codons 1021-1035.
The APC VCEP version 2.1 states that BP1 is applicable to APC missense variants except variants in the first 15-amino-acid repeat of the beta-catenin-binding domain, codons 1021-1035.The assessed variant is missense p.Arg2066Gly at codon 2066, which is outside codons 1021-1035.
cspec ↗
Assessed · not applied · 5 not met · 10 not assessed
Pathogenic
PS1 Not met: p.Arg2066Gly matches neither of the APC VCEP's two established likely pathogenic missense changes, p.Asn1026Ser or p.Ser1028Arg.
PS2 Not assessed: no de novo score, parental genotypes, or confirmed maternity and paternity are documented for APC c.6196A>G.
PS3 Not assessed: the exact-variant report tested other APC variants, with no validated damaging assay result reported for p.Arg2066Gly.
PS4 Not assessed: APC R2066G was reported in one patient, but the adenoma count needed for the VCEP phenotype-point thresholds is unspecified.
PM2 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.
PM5 Not met: no pathogenic or likely pathogenic alternate missense variant at APC residue Arg2066 was identified for comparison with p.Arg2066Gly.
PM6 Not assessed: the only variant-specific report describes R2066G as inherited but provides no parental results or VCEP de novo score.
PP1 Not assessed: no informative meioses, affected relatives, or family-level segregation data are reported for APC c.6196A>G.
PP3 Not assessed: SpliceAI returned no score, while REVEL 0.572 is below the generic PP3 supporting threshold of 0.644.
Benign
BA1 Not met: gnomAD v4.1 Popmax Filtering AF 2.314e-05 is below the APC VCEP BA1 threshold of 0.001.
BS2 Not assessed: gnomAD v4.1 reports 0 homozygotes, but no qualifying healthy-individual data are available to evaluate the alternative 10-point BS2 branch.
BS3 Not assessed: no exact-variant assay showed wild-type-like APC function or normal splicing for p.Arg2066Gly under the VCEP BS3 requirements.
BS4 Not assessed: no affected non-carrier relative or phenotype-point score is documented for APC c.6196A>G.
BP2 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.
BP5 Not assessed: multiple colorectal adenomas are reported, but no pathogenic alternate-gene result is documented to satisfy the APC BP5 rule.
N/A · 11 PVS1 · PM1 · PM3 · PM4 · PP2 · PP4 · PP5 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 2.35442e-05; MAF= 0.00235%, 38/1613984 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.1357e-05; MAF= 0.00314%, 37/1179958 alleles, homozygotes = 0); grpmax FAF= 2.314e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.08903e-06; MAF= 0.00071%, 2/282126 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.55598e-05; MAF= 0.00156%, 2/128536 alleles, homozygotes = 0).
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0024% · 38 / 1,613,984
0 hom · FAF 0.0023%
European (non-Finnish)
37 / 1,179,958
0.0031%
Remaining individuals
1 / 62,482
0.0016%
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.00071% · 2 / 282,126
0 hom
European (non-Finnish)
2 / 128,536
0.0016%
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (9 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 188063)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.572. BayesDel score = 0.333397.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. APC, a tumor suppressor involved in WNT signaling, is recurrently altered in colorectal cancer.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104567844, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 8 PMIDs not cited in assessment
11598466 ↗ Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation. CLINVAR
15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR
18199528 ↗ Multiple rare nonsynonymous variants in the adenomatous polyposis coli gene predispose to colorectal adenomas. CLINVAR
21859464 ↗ Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer? CLINVAR
25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR
25452455 ↗ Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. CLINVAR
25645574 ↗ ACG clinical guideline: Genetic testing and management of hereditary gastrointes CLINVAR
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint co CLINVAR