5-112843311-A-G
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_000038.6(APC):āc.7717A>Gā(p.Ile2573Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000632 in 1,613,566 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. I2573F) 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.7717A>G | p.Ile2573Val | missense_variant | 16/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.7717A>G | p.Ile2573Val | missense_variant | 16/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000877 AC: 22AN: 250818Hom.: 0 AF XY: 0.0000590 AC XY: 8AN XY: 135546
GnomAD4 exome AF: 0.0000630 AC: 92AN: 1461374Hom.: 0 Cov.: 34 AF XY: 0.0000564 AC XY: 41AN XY: 727042
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5AN XY: 74370
ClinVar
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 08, 2019 | - - |
Uncertain significance, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 02, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 21, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27600092, 22703879, 21859464, 25637381, 22975805, 18199528, 31159747) - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 13, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 07, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 20, 2018 | 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. - |
not specified Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 24, 2017 | 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: This variant has been reported in 2 individuals with colorectal adenomas and 1 individual with no cancer. The variant has a Max MAF of 0.03% in ExAC (18 alleles) and 0.02% in gnomAD (21 alleles). Frequency too high for disease? It is classified with 2 stars in ClinVar as VUS by Invitae, Ambry, GeneDx, CSER_CC_NCGL, and Biesecker lab. 10 non-mammals have a Val at this position. - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 11, 2023 | Variant summary: APC c.7717A>G (p.Ile2573Val) 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 8.8e-05 in 250818 control chromosomes, predominantly at a frequency of 0.00018 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.7717A>G has been reported in the literature in and individual affected with Colorectal Adenomas (Azzopard_2008) without evidence for causality. This report does not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 18199528). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=6) and VUS (n=6). Based on the evidence outlined above, the variant was classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Familial adenomatous polyposis 1 Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 05, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 22, 2023 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | - - |
Colorectal adenoma Uncertain:1
Uncertain significance, no assertion criteria provided | research | CSER _CC_NCGL, University of Washington | Jun 01, 2014 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at