chr5-112815508-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2
The NM_000038.6(APC):c.848G>A(p.Arg283Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000041 in 1,611,066 control chromosomes in the GnomAD database, with no homozygous occurrence. 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R283G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.848G>A | p.Arg283Gln | missense_variant | 9/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.848G>A | p.Arg283Gln | missense_variant | 9/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152028Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000836 AC: 21AN: 251064Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135666
GnomAD4 exome AF: 0.0000425 AC: 62AN: 1459038Hom.: 0 Cov.: 30 AF XY: 0.0000317 AC XY: 23AN XY: 725892
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152028Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74230
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 17, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 26, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 13, 2019 | 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 22, 2016 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 29, 2021 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Mar 18, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 14, 2020 | Variant summary: APC c.848G>A (p.Arg283Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251064 control chromosomes. The observed variant frequency is approximately 1.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), suggesting that the variant is benign. c.848G>A has been reported in the literature in individuals affected with Lynch Syndrome (Yurgelun_2015). This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign n=3, VUS n=3). Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 01, 2019 | This variant is associated with the following publications: (PMID: 29684080, 27882345, 25980754, 25801821) - |
APC-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 08, 2023 | 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