Submissions for variant NM_000038.6(APC):c.3083G>T (p.Ser1028Ile)

gnomAD frequency: 0.00001  dbSNP: rs1114167617

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV002526253	SCV003836598	likely pathogenic	Familial adenomatous polyposis 1	2023-02-25	reviewed by expert panel	curation	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).
Invitae	RCV003537065	SCV000647422	uncertain significance	Familial adenomatous polyposis 1	2017-07-19	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with APC-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with isoleucine at codon 1028 of the APC protein (p.Ser1028Ile). The serine residue is highly conserved and there is a large physicochemical difference between serine and isoleucine.
Ambry Genetics	RCV001018532	SCV001179782	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-05-19	criteria provided, single submitter	clinical testing	The p.S1028I variant (also known as c.3083G>T), located in coding exon 15 of the APC gene, results from a G to T substitution at nucleotide position 3083. The serine at codon 1028 is replaced by isoleucine, an amino acid with dissimilar properties. Another likely pathogenic variant at the same nucleotide position, p.S1028N (c.3083G>A), has segregated with disease in a family with attenuated familial adenomatous polyposis (AFAP) and colorectal cancer (Ambry internal data). In addition, internal structural analysis for the p.S1028N variant indicated that this lies on the protein interface important for β-Catenin binding (Ambry internal data). The p.S1028I amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001724055	SCV001957042	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001724055	SCV001969774	uncertain significance	not provided		no assertion criteria provided	clinical testing