Submissions for variant NM_000038.6(APC):c.4336G>A (p.Ala1446Thr)

gnomAD frequency: 0.00056  dbSNP: rs146572883

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001719856	SCV000149000	likely benign	not provided	2020-12-24	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 18199528, 24055113, 25980754, 25637381, 21859464, 25318351, 26580448, 25778705)
Ambry Genetics	RCV000115091	SCV000172883	likely benign	Hereditary cancer-predisposing syndrome	2019-03-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000987571	SCV000259988	likely benign	Familial adenomatous polyposis 1	2024-01-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115091	SCV000910826	benign	Hereditary cancer-predisposing syndrome	2016-03-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000987571	SCV001136910	benign	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000417367	SCV001339030	benign	not specified	2020-03-09	criteria provided, single submitter	clinical testing	Variant summary: APC c.4336G>A (p.Ala1446Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. This is further supported by a functional study, (Azzopardi et al_2008), that demonstrated that the effect of this variant on suppression of beta-catenin regulated transcription (CRT) was identical to the wild-type in well controlled experimental system. The variant allele was found at a frequency of 0.00017 in 284482 control chromosomes, predominantly at a frequency of 0.0016 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.4336G>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (Azzopardi_2008, Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. At least one co-occurrence with another pathogenic variant has been reported internally (PMS2 c.2186_2187delTC, p.Leu729GlnfsX6), providing supporting evidence for a benign role. Five ClinVar submitters (evaluation after 2014) cite the variant as benign (2x) and likely benign (3x). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000417367	SCV001470648	benign	not specified	2019-09-21	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115091	SCV002532026	likely benign	Hereditary cancer-predisposing syndrome	2021-07-23	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002483184	SCV002794748	likely benign	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2022-02-08	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148364	SCV000190056	uncertain significance	Colorectal adenoma	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354016	SCV000591168	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Ala1446Thr variant has been previously described in the literature in 1 of 1382 proband chromosomes of individuals with colorectal cancer. It was not identified in any of the 1938 control chromosomes evaluated (Azzopardi 2008, Minde 2011). However, this variant is identified in the dbSNP database (ID:rs146572883) and the exome variant server database in 5 of 4339 chromosomes increasing the likelihood this may be a low frequency variant in certain populations of origin. This residue is not conserved in mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In addition, this variant is identified in an individual with a co-occuring pathogenic variant, increasing the likelihood this variant does not have clinical significance. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000417367	SCV000691749	uncertain significance	not specified		no assertion criteria provided	clinical testing