ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4072G>A (p.Ala1358Thr) (rs139618756)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129585 SCV000184368 likely benign Hereditary cancer-predisposing syndrome 2019-05-06 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Internal frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Other data supporting benign classification
GeneDx RCV000588058 SCV000209521 uncertain significance not provided 2018-10-30 criteria provided, single submitter clinical testing This variant is denoted APC c.4072G>A at the cDNA level, p.Ala1358Thr (A1358T) at the protein level, and results in the change of an Alanine to a Threonine (GCG>ACG). This variant has been observed in at least three individuals with colon cancer, in two pediatric patients with acute leukemia, and in individuals with breast or kidney cancer (Tung 2015, Zhang 2015, Raskin 2017, Yurgelun 2017, Yehia 2018). APC Ala1358Thr was observed at an allele frequency of 0.01% (18/126,066) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the 20-amino acid repeat beta-catenin down-regulating domain (Azzopardi 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Ala1358Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000167896 SCV000218542 likely benign Familial adenomatous polyposis 1 2020-12-08 criteria provided, single submitter clinical testing
Counsyl RCV000167896 SCV000488249 uncertain significance Familial adenomatous polyposis 1 2016-02-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588058 SCV000600094 uncertain significance not provided 2019-06-20 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129585 SCV000681645 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-17 criteria provided, single submitter clinical testing This missense variant replaces alanine with threonine at codon 1358 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer and suspected Lynch syndrome (PMID: 25980754, 28135145, 29212164). This variant has also been identified in 22/282130 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000211912 SCV000694044 uncertain significance not specified 2020-09-28 criteria provided, single submitter clinical testing Variant summary: APC c.4072G>A (p.Ala1358Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 250742 control chromosomes, predominantly at a frequency of 0.00017 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 2.4 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.4072G>A has been reported in the literature in individuals affected with various tumor phenotypes, including breast cancer, colorectal cancer, suspected Lynch syndrome and in cell lines harboring known and distinct somatic mutations such as EGFR exon 19 deletions (example, Yurgelun_2015, Zhang_2015, Yurgelun_2015, Raskin_2017, Toth_2018, Mancini_2019, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four labs classified the variant as VUS while two classified as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000211912 SCV000691745 uncertain significance not specified no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000167896 SCV001552318 uncertain significance Familial adenomatous polyposis 1 no assertion criteria provided clinical testing The APC p.Ala1358Thr variant was identified in 5 of 11044 proband chromosomes (frequency: 0.0005) from individuals or families with Lynch syndrome, breast cancer, or colorectal cancer and was not identified in 2012 control chromosomes from healthy individuals (Raskin 2017,Tung 2015, Yurgelun 2015, Yurgelun 2017). The variant was also identified in dbSNP (ID: rs139618756) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics, and five other submitters), Cosmic (2x), and MutDB. The variant was not identified in COGR, LOVD 3.0, UMD-LSDB, or Zhejiang University databases. The variant was identified in control databases in 19 of 276468 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 18 of 126066 chromosomes (freq: 0.0001) and Latino in 1 of 34394 chromosomes (freq: 0.00003); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala1358 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact 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. This variant is classified as a variant of uncertain significance.

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