rs141582813
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6
The NM_000038.6(APC):c.1121G>A(p.Arg374Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,858 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. R374W) has been classified as Uncertain significance.
Frequency
Consequence
NM_000038.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.1121G>A | p.Arg374Gln | missense_variant | 10/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.1121G>A | p.Arg374Gln | missense_variant | 10/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152128Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250836Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135558
GnomAD4 exome AF: 0.0000226 AC: 33AN: 1461730Hom.: 0 Cov.: 33 AF XY: 0.0000179 AC XY: 13AN XY: 727156
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152128Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74308
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Sep 19, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 19, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 16, 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. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 17, 2023 | The p.R374Q variant (also known as c.1121G>A), located in coding exon 9 of the APC gene, results from a G to A substitution at nucleotide position 1121. The arginine at codon 374 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 17, 2023 | This missense variant replaces arginine with glutamine at codon 374 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 performed for this variant. This variant has been reported in at least one family affected with familial adenomatous polyposis (Universal Mutation Database; PMID: 24599579). This variant was also reported in an individual affected with colon adenocarcinoma, and an individual affected with kidney clear cell carcinoma (PMID: 29684080). This variant has been identified in 3/250836 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. - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | APC: PP3, BP1, BS4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 23, 2021 | - - |
Familial multiple polyposis syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia | Aug 19, 2015 | - - |
Carcinoma of colon Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The APC, p.Arg374Gln variant was identified in dbSNP (ID: rs141582813), Exome Aggregation Consortium (ExAC) database, the ClinVar database (classified as an uncertain significance variant by Ambry Genetics) and UMD (2X as a neutral variant). This variant was identified in the Exome Variant Server project in 1 of 8600 European American alleles, the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 2 of 66586 chromosomes (2 individuals) from a population of European (Non-Finnish) individuals, although this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The p.Arg374 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance. - |
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 | Dec 01, 2023 | This missense variant replaces arginine with glutamine at codon 374 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in at least one family affected with familial adenomatous polyposis with reported absence of cosegregation (Universal Mutation Database; PMID: 24599579). This variant was also reported in an individual affected with colon adenocarcinoma, and an individual affected with kidney clear cell carcinoma (PMID: 29684080). This variant has been identified in 3/250836 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