5-112839954-A-G
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000038.6(APC):āc.4360A>Gā(p.Lys1454Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000474 in 1,614,122 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict 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
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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APC | ENST00000257430.9 | c.4360A>G | p.Lys1454Glu | missense_variant | Exon 16 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.228+10982A>G | intron_variant | Intron 3 of 7 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes AF: 0.00246 AC: 374AN: 152130Hom.: 4 Cov.: 32
GnomAD3 exomes AF: 0.000597 AC: 150AN: 251232Hom.: 0 AF XY: 0.000471 AC XY: 64AN XY: 135780
GnomAD4 exome AF: 0.000261 AC: 382AN: 1461874Hom.: 4 Cov.: 33 AF XY: 0.000224 AC XY: 163AN XY: 727240
GnomAD4 genome AF: 0.00252 AC: 383AN: 152248Hom.: 5 Cov.: 32 AF XY: 0.00255 AC XY: 190AN XY: 74440
ClinVar
Submissions by phenotype
not specified Benign:7
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Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency high for disorder; multiple papers question pathogenicity -
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BS1, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Hereditary cancer-predisposing syndrome Benign:4
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BA1, BP1 c.4360A>G, located in exon 16 of the APC gene, is predicted to result in the substitution of lysine by glutamic acid at codon 1454, p.(Lys1454Glu)(BP1). This variant is found in 194/23608 at a filtering allele frequency of 0.72% in the African population of the gnomAD v2.1.1 database non-cancer data set (BA1). The SpliceAI algorithm predicts no significant impact on splicing. The REVEL meta-predictor score for this variant (0.554) is indeterminate regarding the effect that it may have on protein function according to Pejaver 2022 thresholds (PMID: 36413997). In addition, the variant was also identified in the ClinVar database (18x likely benign, 6x benign) and in LOVD database (1x uncertain significance). Based on currently available information, c.4360A>G is classified as a benign variant according to ClinGen-APC Guidelines version v1. -
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This alteration is classified as 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. -
Familial adenomatous polyposis 1 Benign:2
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Familial multiple polyposis syndrome Uncertain:1
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Colorectal adenoma Uncertain:1
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APC-Associated Polyposis Disorders Benign:1
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Familial colorectal cancer Benign:1
The APC p.Lys1454Glu variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was identified in ClinVar (Conflicting interpretations of pathogencitiy. Benign(6);Likely benign(4);Uncertain significance(1) ) and Cosmic (Reported x5 Confirmed somatic, identified in tumor tissue from urinary tract (x3), prostate, and haematopoetic and lymphoid tissue) databases. The variant was identified in control databases in 228 of 282622 chromosomes at a frequency of 0.0008067 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 206 of 24960 chromosomes (freq: 0.008253), Latino in 16 of 35416 chromosomes (freq: 0.000452), Other in 3 of 7214 chromosomes (freq: 0.000416), European (Finnish) in 1 of 25120 chromosomes (freq: 0.00004), European (non-Finnish) in 2 of 128990 chromosomes (freq: 0.000016), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Lys1454 residue is conserved in mammals but not in more distantly related organisms, however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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. One functional study found that the p.Lys1454Glu variant suppresses beta-catenin mediated transcription at a level similar to wild-type APC in a cell culture assay, and is therefore predicted to have no effect on APC protein function (Azzopardi_2008_PMID:18199528). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
not provided Benign:1
Variant summary: The APC c.4360A>G (p.Lys1454Glu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant. This variant is not located in any known domain/repeat (InterPro). This variant was found in 68/123380 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0053867 (56/10396). This frequency is about 75 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In literature, the variant has also been reported in patients of various cancer phenotypes (such as FAP, prostate cancer, hepatic cancer, CRC, bladder cancer and B-cell lymphoma) including somatic occurrences, however, without strong evidence for causality. One functional study showed that this variant has a normal effect in an in vitro beta-cateninregulated transcription (CRT) assay (Azzopardi_2008). Multiple clinical labs have classified this variant as benign/likely benign (3 labs) to uncertain significance (1 lab and 1 database). Taken together, this variant has currently been classified as a Likely Benign. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at