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.3084T>A (p.Ser1028Arg)

CA10578350

233215 (ClinVar)

Gene: APC
Condition: familial adenomatous polyposis 1
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f412a530-ecd2-4ceb-bd23-0b0081fee028

HGVS expressions

NM_000038.6:c.3084T>A
NM_000038.6(APC):c.3084T>A (p.Ser1028Arg)
NC_000005.10:g.112838678T>A
CM000667.2:g.112838678T>A
NC_000005.9:g.112174375T>A
CM000667.1:g.112174375T>A
NC_000005.8:g.112202274T>A
NG_008481.4:g.151158T>A
ENST00000257430.9:c.3084T>A
ENST00000257430.8:c.3084T>A
ENST00000502371.2:n.1437T>A
ENST00000507379.5:c.3030T>A
ENST00000508376.6:c.3084T>A
ENST00000508624.5:c.*2406T>A
ENST00000512211.6:c.3084T>A
ENST00000520401.1:n.230+9706T>A
NM_000038.5:c.3084T>A
NM_001127510.2:c.3084T>A
NM_001127511.2:c.3030T>A
NM_001354895.1:c.3084T>A
NM_001354896.1:c.3138T>A
NM_001354897.1:c.3114T>A
NM_001354898.1:c.3009T>A
NM_001354899.1:c.3000T>A
NM_001354900.1:c.2961T>A
NM_001354901.1:c.2907T>A
NM_001354902.1:c.2811T>A
NM_001354903.1:c.2781T>A
NM_001354904.1:c.2706T>A
NM_001354905.1:c.2604T>A
NM_001354906.1:c.2235T>A
NM_001127510.3:c.3084T>A
NM_001127511.3:c.3030T>A
NM_001354895.2:c.3084T>A
NM_001354896.2:c.3138T>A
NM_001354897.2:c.3114T>A
NM_001354898.2:c.3009T>A
NM_001354899.2:c.3000T>A
NM_001354900.2:c.2961T>A
NM_001354901.2:c.2907T>A
NM_001354902.2:c.2811T>A
NM_001354903.2:c.2781T>A
NM_001354904.2:c.2706T>A
NM_001354905.2:c.2604T>A
NM_001354906.2:c.2235T>A

Likely Pathogenic

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Insufficient Evidence"
Met criteria codes 5
PS4_Moderate PP1_Moderate PM2_Supporting PS3_Supporting PM5_Supporting
Not Met criteria codes 1
PS1

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.3084T>A variant in APC is a missense variant predicted to cause the substitution of serine by arginine at amino acid position 1028 p.(Ser1028Arg). This variant has been reported in 6 probands meeting phenotypic criteria, resulting in a total phenotype score of 3 (PS4_Moderate; Ambry Genetics internal data). This variant has been reported to segregate with FAP in 3 meioses in 2 families (6 meiosis in total) (PP1_Moderate; Ambry Genetics internal data). This variant is demonstrated to increased β-catenin regulated transcription activity and decreased binding to β-catenin by surface plasmon resonance (PS3_Supporting, Barcelona internal data). Another missense variant c.3083G>T (p.Ser1028Ile) in the same codon has been classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancers/ Polyposis VCEP (PM5_Supporting). 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_Moderate, PP1_Moderate, PS3_Supporting, PM2_Supporting, PM5_Supporting (VCEP Specification version 1; date of approval: 12/12/2022).
Met criteria codes
PS4_Moderate
This variant has been reported in 6 probands meeting phenotypic criteria, resulting in a total phenotype score of 3 (PS4_Moderate, Ambry Genetics, Invitae internal data).
PP1_Moderate
This variant has been reported to segregate with FAP in 3 meioses in 2 families (6 meiosis in total) (PP1_moderate; Ambry Internal data).
PM2_Supporting
This variant is absent from gnomAD v2.1.1 (PM2_Supporting).
PS3_Supporting
PS3_Supporting (increased β-catenin regulated transcription activity and decreased binding to β-catenin by surface plasmon resonance, internal data).
PM5_Supporting
Another missense variant c.3083G>T (p.Ser1028Ile) in the same codon has been classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancers/ Polyposis VCEP.
Not Met criteria codes
PS1
The amino acid change (p.Ser1028Arg) resulting from a different nucleotide change c.3084T>G has been classified as a variant of unknown significance for FAP according to the APC-VCEP evidence codes (internal data Ambry and Invitae) (PS1_variable not met).
Approved on: 2023-02-25
Published on: 2023-03-14
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