rs369721828
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000038.6(APC):c.8261G>A(p.Ser2754Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000044 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 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. S2754G) 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 -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.8261G>A | p.Ser2754Asn | missense_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.8261G>A | p.Ser2754Asn | missense_variant | 16/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152114Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000836 AC: 21AN: 251092Hom.: 0 AF XY: 0.0000663 AC XY: 9AN XY: 135698
GnomAD4 exome AF: 0.0000452 AC: 66AN: 1461776Hom.: 0 Cov.: 34 AF XY: 0.0000413 AC XY: 30AN XY: 727190
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152114Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74294
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | May 03, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 23, 2016 | - - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 13, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 03, 2015 | 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 Uncertain:2Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 03, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 22, 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. - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 20, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | APC: BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 02, 2020 | This variant is associated with the following publications: (PMID: 27978560, 25203624) - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 24, 2017 | Variant summary: The APC c.8261G>A (p.Ser2754Asn) variant located in the EB-1 binding domain (InterPro) involves the alteration of a non-conserved nucleotide and 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant was found in 21/276830 control chromosomes, predominantly observed in the Ashkenazi Jewish subpopulation at a frequency of 0.001579 (16/10136). This frequency is about 22 times the estimated maximal expected allele frequency of a pathogenic APC variant (0.0000714), suggesting this is likely a benign polymorphism found primarily in Ashkenazi Jewish individuals. A publication, Pearlman_2017, cites the variant in a female diagnosed with colorectal cancer, however, limited information is provided (ie, lack of cosegregation data). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as "uncertain significance" or "benign." Taken together, this variant is classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Classic or attenuated familial adenomatous polyposis Benign:1
Likely benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | - - |
APC-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 13, 2020 | 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