5-112843662-G-A
Variant summary
Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2
The NM_000038.6(APC):c.8068G>A(p.Ala2690Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00138 in 1,613,912 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2690P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.8068G>A | p.Ala2690Thr | missense_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.8068G>A | p.Ala2690Thr | missense_variant | 16/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00145 AC: 221AN: 152082Hom.: 2 Cov.: 32
GnomAD3 exomes AF: 0.00238 AC: 599AN: 251260Hom.: 3 AF XY: 0.00250 AC XY: 339AN XY: 135798
GnomAD4 exome AF: 0.00137 AC: 2009AN: 1461712Hom.: 7 Cov.: 34 AF XY: 0.00142 AC XY: 1032AN XY: 727164
GnomAD4 genome AF: 0.00145 AC: 221AN: 152200Hom.: 2 Cov.: 32 AF XY: 0.00191 AC XY: 142AN XY: 74426
ClinVar
Submissions by phenotype
not specified Benign:6
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 30, 2018 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 29, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 28, 2016 | 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: ExAC: 1.5% (102/6614) Finnish; ClinVar: 3 B, 1 VUS - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 02, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 12, 2018 | - - |
Hereditary cancer-predisposing syndrome Benign:5
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 22, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | May 07, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 30, 2014 | 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. - |
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 21, 2020 | - - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Apr 05, 2018 | - - |
Familial adenomatous polyposis 1 Benign:3
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, no assertion criteria provided | clinical testing | Pathway Genomics | Nov 06, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 12, 2024 | This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. - |
Carcinoma of colon Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The APC p.Ala2690Thr variant was not identified in the literature. The variant was identified in dbSNP (rs140868933) as “with other allele”, ClinVar (classified as benign by Invitae, Ambry Genetics, GeneDx, Color and 4 other submitters and likely benign by True Health Diagnostics and 1 other submitter), LOVD 3.0 (observed 6x) and UMD-LSDB (observed 2x). The variant was identified in control databases in 663 of 282,646 chromosomes (3 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Finnish in 354 of 25,120 chromosomes (freq: 0.01), Other in 18 of 7220 chromosomes (freq: 0.002), European in 264 of 128,976 chromosomes (freq: 0.002), South Asian in 19 of 30,616 chromosomes (freq: 0.0006), Latino in 6 of 35,434 chromosomes (freq: 0.0002), African in 2 of 24,962 chromosomes (freq: 0.00008), while the variant was not observed in the Ashkenazi Jewish, and East Asian populations. The p.Ala2690Thr residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | APC: BP4, BS1 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at