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

gnomAD frequency: 0.00006  dbSNP: rs372305287

Total submissions: 21

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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148360	SCV000254035	benign	Familial adenomatous polyposis 1	2024-01-31	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	2023-04-09	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: 18199528, 21859464, 25142776, 25980754, 31285513), but has also been observed in healthy individuals (PMID: 24728327). 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	2024-01-02	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, Guindalini_2022) 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). The following publications have been ascertained in the context of this evaluation (PMID: 18199528, 24728327, 23085758, 35264596, 25142776, 27009842, 31285513, 21859464, 36672847, 26976419, 25980754, 26580448, 28828701). Sixteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (B/LB n=6, VUS n=10). 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.
Mendelics	RCV004700415	SCV000838148	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.
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
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120031	SCV002550653	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590816	SCV003916969	likely benign	not provided	2023-09-01	criteria provided, single submitter	clinical testing	APC: BP1, BP4
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115120	SCV004228169	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-24	criteria provided, single submitter	clinical testing
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
PreventionGenetics, part of Exact Sciences	RCV004739384	SCV000805464	likely benign	APC-related disorder	2024-09-24	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Molecular Oncology Laboratory, Hospital Clínico San Carlos	RCV000148360	SCV000844925	uncertain significance	Familial adenomatous polyposis 1	2018-06-01	no assertion criteria provided	clinical testing