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

gnomAD frequency: 0.00006  dbSNP: rs139618756

Total submissions: 13

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	This alteration is classified as likely 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.
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	RCV003315877	SCV000218542	likely benign	Familial adenomatous polyposis 1	2024-01-30	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	2023-08-02	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with colorectal cancer (PMIDs: 29212164 (2017), 28135145 (2017)), breast cancer (PMID: 25186627 (2015)), lung cancer (PMID: 29723602 (2018)), and pancreatic cancer (PMID: 32255556 (2020)). The frequency of this variant in the general population, 0.00016 (20/128560 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000129585	SCV000681645	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	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 or suspected Lynch syndrome (PMID: 25980754, 28135145, 29212164), and kidney cancer (PMID: 29684080). 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	likely benign	not specified	2021-09-20	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 as a VUS in settings of multigene panel testing 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. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=4). At-least one of these submitters reports an unspecified co-occurrence with a mutation in another gene that clearly explains a proband's phenotype as the basis of their classification as likely benign. Based on the evidence outlined above, the variant was re-classified as likely benign.
Sema4, Sema4	RCV000129585	SCV002536270	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000167896	SCV002584749	uncertain significance	Familial adenomatous polyposis 1	2022-07-18	criteria provided, single submitter	clinical testing	The APC c.4072G>A (p.Ala1358Thr) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with a personal and/or family history of colorectal cancer (PMID: 28135145, 29212164). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Myriad Genetics, Inc.	RCV003315877	SCV004018765	uncertain significance	Familial adenomatous polyposis 1	2023-02-21	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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.
Genetic Services Laboratory, University of Chicago	RCV000211912	SCV003839748	uncertain significance	not specified	2022-05-18	no assertion criteria provided	clinical testing	DNA sequence analysis of the APC gene demonstrated a sequence change, c.4072G>A, in exon 16 that results in an amino acid change, p.Ala1358Thr. This sequence change has been described in the gnomAD database with a frequency of 0.015557% in the non-Finnish European subpopulation (dbSNP rs139618756). The p.Ala1358Thr change affects a highly conserved amino acid residue located in a domain of the APC protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala1358Thr substitution. This sequence change has been previously described in individuals with colorectal cancer, kidney cancer, and in individuals with a clinical suspicious of Lynch syndrome (PMID: 25980754, 28135145, 29684080, 29212164). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ala1358Thr change remains unknown at this time.