chr5-112767285-G-A
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000038.6(APC):c.317G>A(p.Arg106His) variant causes a missense change. The variant allele was found at a frequency of 0.0000527 in 1,614,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R106C) 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 -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.317G>A | p.Arg106His | missense_variant | 4/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.317G>A | p.Arg106His | missense_variant | 4/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152192Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251464Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135904
GnomAD4 exome AF: 0.0000540 AC: 79AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42AN XY: 727226
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152310Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74470
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 106 of the APC protein (p.Arg106His). This variant is present in population databases (rs201764637, gnomAD 0.02%). This missense change has been observed in individual(s) with familial adenomatous polyposis (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 41524). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 11, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The APC p.Arg106His variant was not identified in the literature, nor was it identified in NHLBI GO Exome Sequencing Project, GeneInsight COGR, COSMIC, MutDB, UMD, InSiGHT Colon Cancer Gene Variant Database (LOVD), or the Zhejiang Colon Cancer Database (LOVD). The variant was identified in dbSNP (ID: rs201764637) as “With Uncertain significance allele”, the Clinvitae database and ClinVar database (classification uncertain significance, submitters Counsyl and Biesecker Lab/Human Development Section NIH), the 1000 Genomes Project, the NHLBI Exome Sequencing Project, the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.002), HAPMAP-SAS in 1 of 978 chromosomes (frequency: 0.001), the genome Aggregation Database (Feb 27, 2017) in 13 of 277212 chromosomes (freq. 0.00005) and the Exome Aggregation Consortium database (August 8th 2016) in 5 of 121334 chromosomes (freq. 0.00004) in the following population: South Asian in 5 of 16512 chromosomes (freq. 0.0003), but was not seen in African, East Asian, European, Latino and Other populations increasing the likelihood that this may be a low frequency benign variant in certain populations of origin. In addition the variant was identified in this case as co-occurring with a pathogenic APC variant (c.937_938delGA, p.Glu313AsnfsX13), increasing the likelihood that the variant may not have clinical significance. In addition the variant was identified by our laboratory in a patient with polyposis as co-occurring with a pathogenic APC variant (c.937_938delGA, p.Glu313AsnfsX13), increasing the likelihood that the variant may not have clinical significance . The p.Arg106 residue is conserved in mammals and the variant amino acid His is present in the African clawed frog suggesting that this amino acid substitution may be tolerated. 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 22, 2023 | This variant is considered likely benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. - |
not specified Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 23, 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: Reported in 1 proband with cancer and a clinseq participant - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 05, 2020 | Variant summary: APC c.317G>A (p.Arg106His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.6e-05 in 284804 control chromosomes, predominantly at a frequency of 0.00023 within the South Asian subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.317G>A has been reported in the literature in at least an individual affected with familial adenomatous polyposis (Azzopard_2008). This report however, 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. Nine other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 16, 2017 | - - |
not provided Uncertain:3
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 | GeneDx | Jan 25, 2023 | In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29422544, 21859464, 22703879, 29413759, 29245953, 18199528) - |
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 20, 2017 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 01, 2023 | This missense variant replaces arginine with histidine at codon 106 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with adenomatous polyposis (PMID: 18199528, 21859464). This variant has also been identified in 13/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 20, 2022 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 14, 2021 | 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 multiple polyposis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Classic or attenuated familial adenomatous polyposis Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | This missense variant replaces arginine with histidine at codon 106 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with adenomatous polyposis (PMID: 18199528, 21859464). This variant has also been identified in 13/282866 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at