Submissions for variant NM_000038.6(APC):c.4420G>A (p.Ala1474Thr)

gnomAD frequency: 0.00324  dbSNP: rs139387758

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV000987573	SCV003836603	benign	Familial adenomatous polyposis 1	2023-02-26	reviewed by expert panel	curation	The c.4420G>A variant in APC is a missense variant predicted to cause the substitution of Alanine by Threonine at amino acid position 1474 (p.Ala1474Thr). The highest population minor allele frequency of this variant in gnomAD v2.1.1 (non-cancer) is 1.13% in the African/African American population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel’s (HCCP VCEP) threshold (0.1%) for BA1, and therefore meets this criterion (BA1). Functional study of beta-catenin-regulated transcription assays indicate that this alteration suppresses CRT as effectively as wild type (BS3_Supporting; PMID: 18199528). Finally, APC is defined by the HCCP VCEP as a gene for which primarily truncating variants are known to cause disease (BP1). In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BA1, BP1, BS3_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).
GeneDx	RCV000759431	SCV000167009	benign	not provided	2018-12-04	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18199528, 24728327, 24055113, 24861525, 25637381, 21859464, 26332594)
Ambry Genetics	RCV000129100	SCV000183811	benign	Hereditary cancer-predisposing syndrome	2015-01-04	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV003650378	SCV000252587	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000321870	SCV000452012	likely benign	APC-Associated Polyposis Disorders	2018-11-29	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000120040	SCV000602521	likely benign	not specified	2016-10-27	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120040	SCV000805409	benign	not specified	2017-04-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759431	SCV000888745	benign	not provided	2022-07-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129100	SCV000902635	benign	Hereditary cancer-predisposing syndrome	2016-03-23	criteria provided, single submitter	clinical testing
Mendelics	RCV000987573	SCV001136913	benign	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129100	SCV002534272	benign	Hereditary cancer-predisposing syndrome	2020-03-21	criteria provided, single submitter	curation
ITMI	RCV000120040	SCV000084173	not provided	not specified	2013-09-19	no assertion provided	reference population
CSER _CC_NCGL, University of Washington	RCV000148366	SCV000190058	uncertain significance	Colorectal adenoma	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358624	SCV001554414	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Ala1474Thr variant was identified in 1 of 1382 proband chromosomes (frequency: 0.0007) from individuals or families with colorectal polyps (Azzopardi, 2008). The variant was also identified in dbSNP (ID: rs139387758 as With Uncertain significance allele), ClinVar (3x as benign, 2x as likely benign, 1x as a variant of uncertain significance), Cosmic (2x), LOVD 3.0 (1x as not classified), and UMD-LSDB (1x). The variant was not identified in MutDB or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 290 of 276830 chromosomes (2 homozygous) at a frequency of 0.001, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 270 of 24026 chromosomes (freq: 0.01), Other in 2 of 6456 chromosomes (freq: 0.0003), Latino in 13 of 34404 chromosomes (freq: 0.0004), European Non-Finnish in 4 of 126384 chromosomes (freq: 0.00003), and SouthAsian in 1 of 30774 chromosomes (freq: 0.00003), while the variant was not observed in the Ashkenazi Jewish, East Asian, or Finnish, populations. The p.Ala1474 residue is moderately conserved in mammals, although 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, the clinical significance of this variant cannot be determined with certainty at this time although the available information is suggestive of a benign role. This variant is classified as likely benign.