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
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| APC | ENST00000257430.9 | c.7399C>A | p.Pro2467Thr | missense_variant | Exon 16 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
| ENSG00000258864 | ENST00000520401.1 | n.229-13656C>A | intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes 0.0000723 AC: 11AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000123 AC: 31AN: 251108Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135698
GnomAD4 exome AF: 0.000107 AC: 157AN: 1461756Hom.: 0 Cov.: 34 AF XY: 0.000114 AC XY: 83AN XY: 727170
GnomAD4 genome 0.0000723 AC: 11AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74328
ClinVar
Submissions by phenotype
not specified Uncertain:4Benign:1Other:1
Variant classified as Uncertain Significance - Favor Benign. -
- -
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. -
- -
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. 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). 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). ClinVar contains an entry for this variant (Variation ID: 127318). Based on the evidence outlined above, the variant was classified as likely benign. -
- -
Hereditary cancer-predisposing syndrome Uncertain:3Benign:2
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. -
- -
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. -
- -
- -
Familial adenomatous polyposis 1 Uncertain:1Benign:2
- -
- -
- -
not provided Benign:3
This variant is associated with the following publications: (PMID: 23085758, 24728327, 18199528, 21859464, 25637381, 25980754, 26976419, 27050224, 28805986, 27882345, 28873162, 31285513) -
APC: BP1, BP4 -
- -
Carcinoma of colon Uncertain:1
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
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
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
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:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at