Submissions for variant NM_000038.6(APC):c.3077A>C (p.Asn1026Thr)

dbSNP: rs1114167603

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV003148754	SCV003836596	uncertain significance	Familial adenomatous polyposis 1	2023-02-25	reviewed by expert panel	curation	The c.3077A>C variant in APC is a missense variant predicted to cause the substitution of asparagine by threonine at amino acid position 1026 (p.Asn1026Thr). This variant has been reported in 3 probands with FAP worth 1.5 phenotype points (PS4_Supporting; Ambry Internal Data). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Another missense variant, c.3077A>G (p.Asn1026Ser) in the same codon has been classified as Likely Pathogenic for FAP by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) (PM5_Supporting; PMID 18166348). In summary, due to insufficient evidence, this variant is a Variant of Uncertain Significance for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: PS4_Supporting, PM2_Supporting, and PM5_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).
Ambry Genetics	RCV000491915	SCV000579912	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-06-30	criteria provided, single submitter	clinical testing	The p.N1026T variant (also known as c.3077A>C), located in coding exon 15 of the APC gene, results from an A to C substitution at nucleotide position 3077. The asparagine at codon 1026 is replaced by threonine, an amino acid with similar properties. While this exact alteration has not been reported in the literature to our knowledge, a similar alteration at this same location, p.N1026S (c.3077A>G), has been reported to segregate with disease in a large Spanish attenuated FAP family (Menéndez M et al. Gastroenterology 2008 Jan; 134(1):56-64). Menéndez M et al. further investigated the functional significance of the p.N1026S alteration using an in vitro beta-catenin binding assay and showed it resulted in a functionally altered protein. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353697	SCV000591129	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Asn1026Thr was not identified in the literature, dbSNP, 1000 Genomes Project, NHLBI GO Exome Sequencing Project (ESP, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015), Clinvitae database, COSMIC, Zhejiang Colon Cancer Database (LOVD), ClinVar database, GeneInsight - COGR database, the InSiGHT Colon Cancer Gene Variant Database (LOVD) and UMD. A variant at the same loci, p.Asn1026Ser was identified in the literature and classified as pathogenic based on segregation data and in vivo studies (Menendez 2008). The p.Asn1026 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Mayo Clinic Laboratories, Mayo Clinic	RCV000502196	SCV000691729	uncertain significance	not specified		no assertion criteria provided	clinical testing