ClinVar Miner

Submissions for variant NM_000038.6(APC):c.7399C>A (p.Pro2467Thr)

gnomAD frequency: 0.00006  dbSNP: rs372305287
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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590816 SCV000149029 likely benign not provided 2020-12-01 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23085758, 24728327, 18199528, 21859464, 25637381, 25980754, 26976419, 27050224, 28805986, 27882345, 28873162, 31285513)
Ambry Genetics RCV000115120 SCV000213856 likely benign Hereditary cancer-predisposing syndrome 2018-06-26 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV002228343 SCV000254035 benign Familial adenomatous polyposis 1 2021-12-17 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000120031 SCV000257788 uncertain significance not specified 2015-06-19 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000115120 SCV000681864 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-16 criteria provided, single submitter clinical testing This missense variant replaces proline with threonine at codon 2467 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with FAP or colorectal cancer (PMID: PMID: 18199528, 21859464, 25142776, 25980754, 31285513). This variant has been identified in 31/251108 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 RCV000120031 SCV000694114 likely benign not specified 2022-06-20 criteria provided, single submitter clinical testing Variant summary: APC c.7399C>A (p.Pro2467Thr) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 252470 control chromosomes (gnomAD, Bodian_2014). The observed variant frequency is approximately 2 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 benign. c.7399C>A has been reported in the literature in individuals affected with Familial Adenomatous Polyposis, colorectal cancer, HBOC, ALL and Neuroblastoma (e.g. Azzopardi_2008, Kraus_2015, Yurgelun_2015, Zhang_2015, Tung_2016, Zidan_2017, Lorca_2019, Duz_2021, Lasorsa_2016) but it was also detected in controls (e.g. Bodian_2014). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Furthermore, the variant has been reported to co-occur with a presumably pathogenic APC-LOF variant and APC-LOH deletion in a colorectal cancer tumor-derived specimen. In this study, truncating APC mutations and/or LOH were detected in 75% of CRC's examined supporting a benign role for this variant in disease pathogenesis (Christie_2013). Thirteen ClinVar submitters have assessed the variant since 2014: nine classified the variant as of uncertain significance, three as likely benign, and one as benign. One of the submitters cites evidence of co-occurrence with a mutation in another gene that clearly explains a proband's phenotype (SCV000213856.6). Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine RCV000120031 SCV000711955 uncertain significance not specified 2016-11-18 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign.
PreventionGenetics,PreventionGenetics RCV000590816 SCV000805464 uncertain significance not provided 2017-06-01 criteria provided, single submitter clinical testing
Mendelics RCV000148360 SCV000838148 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000735966 SCV000864155 uncertain significance Colorectal cancer 2016-06-01 criteria provided, single submitter research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 51 year old male diagnosed with colon cancer at age 50. Family history of colorectal cancer and/or polyps. Patient also has the APC c.5026A>G variant. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590816 SCV001133365 likely benign not provided 2020-10-13 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000120031 SCV002068079 uncertain significance not specified 2020-04-16 criteria provided, single submitter clinical testing DNA sequence analysis of the APC gene demonstrated a sequence change, c.7399C>A, in exon 16 that results in an amino acid change, p.Pro2467Thr. This sequence change has been described in the gnomAD database with a frequency of 0.089% in the Ashkenazi Jewish sub-population (dbSNP rs372305287). The p.Pro2467Thr change has previously been reported, in addition to another heterozygous APC sequence change, c.5026A>G (p.Arg1676Gly), in an individual with FAP (PMID: 18199528). The p.Pro2467Thr change has also been reported in an individual reported to have 10-100 colorectal adenomas (PMID: 31285513). The p.Pro2467Thr change affects a highly conserved amino acid residue located in a domain of the APC protein that is known to be functional. The p.Pro2467Thr substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Pro2467Thr change remains unknown at this time.
Sema4,Sema4 RCV000115120 SCV002527590 likely benign Hereditary cancer-predisposing syndrome 2021-04-11 criteria provided, single submitter curation
ITMI RCV000120031 SCV000084162 not provided not specified 2013-09-19 no assertion provided reference population
CSER _CC_NCGL, University of Washington RCV000148360 SCV000190050 likely benign Familial adenomatous polyposis 1 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353987 SCV000591207 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The APC p.Pro2467Thr variant was identified at a frequency of 0.003 or 2 of 1382 proband chromosomes from individuals or families with colorectal adenomas and colorectal cancer, and was not present in 1938 control chromosomes from healthy individuals matched for age, sex and race (Azzopardi 2008, Kraus 2014). In both cases the variant was identified with another variant of uncertain significance, APC p.Arg1676Gly. The variant was also identified in dbSNP (ID: rs372305287) as “other”; NHLBI GO Exome Sequencing Project in 1 of 8598 European American chromosomes; in the Exome Aggregation Consortium database (March 14, 2016) in 16 of 121336 chromosomes (freq. 0.0001) in the following populations: European (Non-Finnish) in 11 of 66702 chromosomes (freq. 0.0002), South Asian in 3 of 16508 chromosomes (freq. 0.0002), Latino in 2 of 11552 chromosomes (freq. 0.0002), but was not seen in African, East Asian, Finnish and other populations; Clinvitae database (3x uncertain significance); ClinVar database (uncertain significance by Ambry Genetics, Invitae, Division of Genomic Diagnostics-the Children’s Hospital Of Philadelphia and GeneDx, and likely benign by University of Washington Medical School, ITMI did not provide a classification); the COGR database (uncertain significance) and UMD (1x with unclassified variant, the variant co-occurred with a non-synonymous variant c.5026A>G, p.Arg1676Gly). In COSMIC, the variant was identified as a confirmed homozygous somatic mutation found in cancer of the large intestine. The p.Pro2467 residue is conserved across mammals, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Threonine (Thr) variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a difference at a 3’ cryptic splice site. However, in a study looking at rare nonsynonomous variants the authors note that multiple rare inherited non-synonymous variants of APC were significantly over represented in patients who did not carry conventional pathogenic mutations in the APC or MUTYH genes. The authors felt that patients with 2 rare non-synonymous heterozygous variants, involved in ß-catenin down-regulation domain of APC protein, are likely to predispose to colorectal adenomas as compared to non FAP/MAP patients. The non-synonymous variants, c.5026A>G, R1676G and c.7399C>A, P2467T were seen together in 1 patient in their cohort and thought to together act as low penetrance disease alleles (Azzopardi 2008). 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.
True Health Diagnostics RCV000115120 SCV000787839 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing
Molecular Oncology Laboratory,Hospital Clínico San Carlos RCV000148360 SCV000844925 uncertain significance Familial adenomatous polyposis 1 2018-06-01 no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000120031 SCV002550653 uncertain significance not specified 2021-11-30 no assertion criteria provided clinical testing

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