Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000038.6(APC):c.3083G>T (p.Ser1028Ile)

CA16028086

469904 (ClinVar)

Gene: APC
Condition: familial adenomatous polyposis 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: a7b67bc5-03df-4624-805a-d991baa8f1f6
Approved on: 2023-02-25
Published on: 2023-03-14

HGVS expressions

NM_000038.6:c.3083G>T
NM_000038.6(APC):c.3083G>T (p.Ser1028Ile)
NC_000005.10:g.112838677G>T
CM000667.2:g.112838677G>T
NC_000005.9:g.112174374G>T
CM000667.1:g.112174374G>T
NC_000005.8:g.112202273G>T
NG_008481.4:g.151157G>T
ENST00000257430.9:c.3083G>T
ENST00000257430.8:c.3083G>T
ENST00000502371.2:n.1436G>T
ENST00000507379.5:c.3029G>T
ENST00000508376.6:c.3083G>T
ENST00000508624.5:c.*2405G>T
ENST00000512211.6:c.3083G>T
ENST00000520401.1:n.230+9705G>T
NM_000038.5:c.3083G>T
NM_001127510.2:c.3083G>T
NM_001127511.2:c.3029G>T
NM_001354895.1:c.3083G>T
NM_001354896.1:c.3137G>T
NM_001354897.1:c.3113G>T
NM_001354898.1:c.3008G>T
NM_001354899.1:c.2999G>T
NM_001354900.1:c.2960G>T
NM_001354901.1:c.2906G>T
NM_001354902.1:c.2810G>T
NM_001354903.1:c.2780G>T
NM_001354904.1:c.2705G>T
NM_001354905.1:c.2603G>T
NM_001354906.1:c.2234G>T
NM_001127510.3:c.3083G>T
NM_001127511.3:c.3029G>T
NM_001354895.2:c.3083G>T
NM_001354896.2:c.3137G>T
NM_001354897.2:c.3113G>T
NM_001354898.2:c.3008G>T
NM_001354899.2:c.2999G>T
NM_001354900.2:c.2960G>T
NM_001354901.2:c.2906G>T
NM_001354902.2:c.2810G>T
NM_001354903.2:c.2780G>T
NM_001354904.2:c.2705G>T
NM_001354905.2:c.2603G>T
NM_001354906.2:c.2234G>T

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 3
PS4 PM2_Supporting PM5_Supporting
Not Met criteria codes 4
PP1 PP3 PP2 BP1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
InSiGHT Hereditary Colorectal Cancer/Polyposis VCEP
The c.3083G>T variant in APC is a missense variant predicted to cause the substitution of serine by isoleucine at amino acid position 1028 (p.Ser1028Ile). This variant has been reported in 6 individuals resulting in a total phenotype score of 4.5 (PS4, Ambry, Invitae, Melbourne internal data). Another missense variant c.3084T>A (p.Ser1028Arg) in the same codon has been classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancers/ Polyposis VCEP (PM5_Supporting). Splicing prediction using SpliceAI and varSEAK revealed no expected effects on splicing due to any of these variants. Finally, this variant is absent from gnomAD v2.1.1 (PM2_Supporting). In summary, this variant is classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS4, PM2_Supporting, and PM5_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).
Met criteria codes
PS4
This variant has been reported in 6 individuals resulting in a total phenotype score of 4.5 (PS4, Ambry, Invitae, Melbourne internal data).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PM5_Supporting
Another missense variant c.3084T>A (p.Ser1028Arg) in the same codon has been classified as pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancers/ Polyposis VCEP (PM5_Supporting). Splicing prediction using SpliceAI and varSEAK revealed no expected effects on splicing due to any of these variants.
Not Met criteria codes
PP1
In 1 meiosis in 1 family (Ambry Internal data).
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP1
Based on our knowledge there are only two amino acid positions with reported likely pathogenic missense variants (p.Asn1026 and p.Ser1028) (PMIDs18166348, 32750050 and personal communication). Therefore, for all variants located in the first 15-amino acid repeat of the β-catenin binding domain (codon 1021-1035) BP1 is not allowed to be used.
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