ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5140G>A (p.Asp1714Asn)

gnomAD frequency: 0.00006  dbSNP: rs148275069
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002228630 SCV000166041 likely benign Familial adenomatous polyposis 1 2021-12-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129088 SCV000183796 likely benign Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000479916 SCV000564574 likely benign not specified 2017-11-22 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587086 SCV000600110 likely benign not provided 2019-08-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000479916 SCV000694069 likely benign not specified 2021-08-19 criteria provided, single submitter clinical testing Variant summary: APC c.5140G>A (p.Asp1714Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 250168 control chromosomes, predominantly at a frequency of 0.00035 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5-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 Non-Finnish European origin. c.5140G>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (e.g. Azzopardi_2008, Out_2015, Rohlin_2017) but has also been reported in patients with other phenotypes, including breast cancer and medulloblastoma (e.g. Tung_2015, Zhang_2015). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Experimental evidence evaluating an impact on protein function, demonstrated the variant alters beta-catenin-regulated transcription (CRT) in vitro (e.g. Azzopardi_2008). However, no definitive conclusions can be drawn about the clinical relevance of this finding. Five ClinVar submitters (evaluation after 2014) cite the variant as likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000587086 SCV000805422 uncertain significance not provided 2014-03-11 criteria provided, single submitter clinical testing
Mendelics RCV000122784 SCV000838131 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129088 SCV000910666 likely benign Hereditary cancer-predisposing syndrome 2016-11-22 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001157159 SCV001318706 uncertain significance APC-Associated Polyposis Disorders 2017-04-27 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001762273 SCV002010874 uncertain significance Colorectal cancer 2021-11-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000479916 SCV002069707 uncertain significance not specified 2019-11-22 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000129088 SCV002535065 uncertain significance Hereditary cancer-predisposing syndrome 2021-11-15 criteria provided, single submitter curation
CSER _CC_NCGL, University of Washington RCV000122784 SCV000190065 uncertain significance Familial adenomatous polyposis 1 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000587086 SCV001552571 likely benign not provided no assertion criteria provided clinical testing The APC p.Asp1714Asn variant was identified in 2 of 1564 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer or adenomatous polyposis and was present in 1 of 1938 control chromosomes (frequency: 0.001) from healthy individuals (Azzopardi 2008, Rohlin 2017). The variant was also identified in dbSNP (ID: rs148275069) as "With Uncertain significance, other allele”, ClinVar (classified as likely benign by GeneDx, Ambry Genetics and Integrated Genetics/Laboratory Corporation of America; and as uncertain significance by five submitters), and in LOVD 3.0. The variant was identified in control databases in 46 of 276088 chromosomes at a frequency of 0.0002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 23960 chromosomes (freq: 0.00008), Other in 2 of 6444 chromosomes (freq: 0.0003), European in 40 of 125810 chromosomes (freq: 0.0003), and Finnish in 2 of 25786 chromosomes (freq: 0.00008), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, or South Asian populations. The p.Asp1714 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Asn variant to the protein; 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) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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