rs76685252
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_000038.6(APC):c.647G>A(p.Arg216Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,606,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. R216G) has been classified as Likely benign.
Frequency
Consequence
NM_000038.6 missense, splice_region
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.647G>A | p.Arg216Gln | missense_variant, splice_region_variant | 7/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.647G>A | p.Arg216Gln | missense_variant, splice_region_variant | 7/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000527 AC: 8AN: 151884Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000400 AC: 10AN: 250290Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135280
GnomAD4 exome AF: 0.0000261 AC: 38AN: 1454642Hom.: 0 Cov.: 29 AF XY: 0.0000235 AC XY: 17AN XY: 723576
GnomAD4 genome ? AF: 0.0000461 AC: 7AN: 152002Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74290
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 216 of the APC protein (p.Arg216Gln). This variant is present in population databases (rs76685252, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer, breast cancer (PMID: 18199528, 28135145, 35264596). ClinVar contains an entry for this variant (Variation ID: 188275). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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 | Jun 06, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 09, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 15, 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 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 24, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 22, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colorectal cancer or adenomas (Azzopardi et al., 2008; Minde et al., 2011; Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 21859464, 28748566, 28873162, 27329244, 18199528, 26332594, 28135145) - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 29, 2024 | The p.R216Q variant (also known as c.647G>A), located in coding exon 6 of the APC gene, results from a G to A substitution at nucleotide position 647. The arginine at codon 216 is replaced by glutamine, an amino acid with highly similar properties. This alteration was reported in a cohort of 691 North Americans, in one individual with 11-99 colorectal adenomas (Azzopardi D et al. Cancer Res. 2008 Jan;68:358-63), and has also been reported in a cohort of individuals with unselected colorectal cancer (Yurgelun MB et al. J. Clin. Oncol. 2017 Apr;35:1086-1095). This amino acid position is not well conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 05, 2016 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 02, 2024 | Variant summary: APC c.647G>A (p.Arg216Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 250290 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in APC causing Familial Adenomatous Polyposis (4e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.647G>A has been reported in the literature in individuals affected with colorectal cancer and breast cancer (examples:Azzopardi_2008, Yurgelun_2017, Guindalini_2022). These report(s) do 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 publications have been ascertained in the context of this evaluation (PMID: 18199528, 35264596, 21859464, 36243179, 26332594, 28135145). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS n=7, likely benign n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
APC-Associated Polyposis Disorders Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Mar 06, 2018 | 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at