ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4336G>A (p.Ala1446Thr) (rs146572883)

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Total submissions: 10
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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 In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s)
Invitae RCV000987571 SCV000259988 likely benign Familial adenomatous polyposis 1 2020-11-15 criteria provided, single submitter clinical testing
Color Health, Inc 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
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

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