chr5-112828924-A-G
Variant summary
Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2
The NM_000038.6(APC):c.1695A>G(p.Glu565Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,613,928 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).
Frequency
Consequence
NM_000038.6 synonymous
Scores
Clinical Significance
Conservation
Publications
- classic or attenuated familial adenomatous polyposisInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
- desmoid tumorInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Genomics England PanelApp
- familial adenomatous polyposis 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
- gastric adenocarcinoma and proximal polyposis of the stomachInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- APC-related attenuated familial adenomatous polyposisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Turcot syndrome with polyposisInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Cenani-Lenz syndactyly syndromeInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
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ACMG classification
Our verdict: Benign. The variant received -19 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.1695A>G | p.Glu565Glu | synonymous_variant | Exon 14 of 16 | 5 | NM_000038.6 | ENSP00000257430.4 | ||
ENSG00000258864 | ENST00000520401.1 | n.180A>G | non_coding_transcript_exon_variant | Exon 3 of 8 | 3 | ENSP00000454861.1 |
Frequencies
GnomAD3 genomes AF: 0.0108 AC: 1646AN: 152184Hom.: 30 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00300 AC: 754AN: 251334 AF XY: 0.00221 show subpopulations
GnomAD4 exome AF: 0.00102 AC: 1490AN: 1461626Hom.: 27 Cov.: 31 AF XY: 0.000913 AC XY: 664AN XY: 727126 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.0108 AC: 1652AN: 152302Hom.: 30 Cov.: 32 AF XY: 0.0108 AC XY: 801AN XY: 74478 show subpopulations
Age Distribution
ClinVar
Submissions by phenotype
not specified Benign:8
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The APC p.Glu565Glu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant is listed in UMD (3X) as a neutral variant (co-occurring with a pathogenic APC variant in one sample), in the ClinVar database (classified as benign by Ambry Genetics), and in the Invitae database (classified as “variant of unknown significance” by Emory Genetics). Three of five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the potential creation of a 5’ splice site; however, this information is not predictive enough to assume pathogenicity. The variant was identified in the literature in 10 of 1695 familial adenomatous polyposis cases (allelic frequency: 0.003); the authors suggest the variant is likely benign due to a co-occurring pathogenic APC variant identified in at least one of these individuals (Kerr 2013). In addition, the variant was identified in several populations at polymorphic allelic frequencies: 1000 Genomes Project (frequency: 0.014), Exome Variant Server ESP project (African American cohort frequency: 0.036, and the ExAC browser (African cohort frequency: 0.038). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
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Hereditary cancer-predisposing syndrome Benign:4
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. -
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Familial adenomatous polyposis 1 Benign:3
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This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
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APC-Associated Polyposis Disorders Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at