rs372305287
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000038.6(APC):c.7399C>A(p.Pro2467Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
APC
NM_000038.6 missense
NM_000038.6 missense
Scores
14
5
Clinical Significance
Conservation
PhyloP100: 2.71
Genes affected
APC (HGNC:583): (APC regulator of WNT signaling pathway) This gene encodes a tumor suppressor protein that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis. Defects in this gene cause familial adenomatous polyposis (FAP), an autosomal dominant pre-malignant disease that usually progresses to malignancy. Mutations in the APC gene have been found to occur in most colorectal cancers, where disease-associated mutations tend to be clustered in a small region designated the mutation cluster region (MCR) and result in a truncated protein product. [provided by RefSeq, Jun 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.15901303).
BP6
Variant 5-112842993-C-A is Benign according to our data. Variant chr5-112842993-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127318.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=7, not_provided=1, Benign=1}. Variant chr5-112842993-C-A is described in Lovd as [Likely_benign].
BS2
High AC in GnomAd4 at 11 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| APC | NM_000038.6 | c.7399C>A | p.Pro2467Thr | missense_variant | 16/16 | ENST00000257430.9 | NP_000029.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | c.7399C>A | p.Pro2467Thr | missense_variant | 16/16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
| ENSG00000258864 | ENST00000520401.1 | n.229-13656C>A | intron_variant | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes 0.0000723 AC: 11AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000123 AC: 31AN: 251108Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135698
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GnomAD4 exome AF: 0.000107 AC: 157AN: 1461756Hom.: 0 Cov.: 34 AF XY: 0.000114 AC XY: 83AN XY: 727170
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GnomAD4 genome 0.0000723 AC: 11AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74328
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:10Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:4Benign:1Other:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 18, 2016 | Variant classified as Uncertain Significance - Favor Benign. - |
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 16, 2020 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Jun 19, 2015 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 02, 2024 | 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. - |
Hereditary cancer-predisposing syndrome Uncertain:3Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 26, 2018 | 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. - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 11, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 09, 2023 | 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. - |
| Uncertain significance, no assertion criteria provided | clinical testing | True Health Diagnostics | Dec 01, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Oct 24, 2023 | - - |
Familial adenomatous polyposis 1 Uncertain:1Benign:2
| Likely benign, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Molecular Oncology Laboratory, Hospital Clínico San Carlos | Jun 01, 2018 | - - |
not provided Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 01, 2020 | This variant is associated with the following publications: (PMID: 23085758, 24728327, 18199528, 21859464, 25637381, 25980754, 26976419, 27050224, 28805986, 27882345, 28873162, 31285513) - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | APC: BP1, BP4 - |
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 13, 2020 | - - |
Carcinoma of colon Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Colorectal cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Jun 01, 2016 | 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. - |
Hereditary cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Sep 11, 2024 | 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. - |
APC-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 24, 2024 | 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). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;M
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Uncertain
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
P;P
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at