5-112775655-A-G
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP3BP6BS2
The NM_000038.6(APC):āc.449A>Gā(p.Lys150Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000616 in 1,608,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. K150I) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
APC | NM_000038.6 | c.449A>G | p.Lys150Arg | missense_variant | 5/16 | ENST00000257430.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
APC | ENST00000257430.9 | c.449A>G | p.Lys150Arg | missense_variant | 5/16 | 5 | NM_000038.6 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000395 AC: 6AN: 152058Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000202 AC: 5AN: 247824Hom.: 0 AF XY: 0.0000299 AC XY: 4AN XY: 133744
GnomAD4 exome AF: 0.0000639 AC: 93AN: 1456346Hom.: 0 Cov.: 29 AF XY: 0.0000552 AC XY: 40AN XY: 724230
GnomAD4 genome AF: 0.0000395 AC: 6AN: 152058Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74286
ClinVar
Submissions by phenotype
Familial adenomatous polyposis 1 Uncertain:4Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 150 of the APC protein (p.Lys150Arg). This variant is present in population databases (rs371085910, gnomAD 0.005%). This missense change has been observed in individual(s) with clinical features of familial adenomatous polyposis (PMID: 18199528). ClinVar contains an entry for this variant (Variation ID: 141928). 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%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Aug 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 17, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 18, 2017 | - - |
Hereditary cancer-predisposing syndrome Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 11, 2023 | This missense variant replaces lysine with arginine at codon 150 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, protein functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer, colorectal adenomas, and rhabdosarcoma in the literature (PMID: 18199528, 21859464, 26580448, 28503720). This variant has been identified in 6/279048 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 10, 2021 | 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. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 01, 2021 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | True Health Diagnostics | Sep 25, 2017 | - - |
not specified Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 22, 2020 | proposed classification - variant undergoing re-assessment, contact laboratory - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 23, 2018 | Variant summary: APC c.449A>G (p.Lys150Arg) 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 2.2e-05 in 273686 control chromosomes. This frequency is not higher than expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis (2.2e-05 vs 7.1e-05), allowing no conclusion about variant significance. c.449A>G has been reported in the literature in individuals affected with breast cancer and colon colorectal adenomas (Azzopardi_2008, Rummel_2017). These reports do not provide unequivocal conclusions about an association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 18, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 18, 2022 | Observed in individuals with a personal history of colorectal adenomas, breast cancer, or other cancers (Azzopardi et al., 2008; Minde et al., 2011; Zhang et al., 2015; Ballinger et al., 2016; Rummel et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 25637381, 21859464, 18199528, 26580448, 27498913, 28152038, 28503720, 16454848, 12070164, 27535533, 11257105, 34301788) - |
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 | Feb 05, 2024 | This missense variant replaces lysine with arginine at codon 150 of the APC protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, protein functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer, colorectal adenomas, and rhabdosarcoma in the literature (PMID: 18199528, 21859464, 26580448, 28503720). This variant has been identified in 6/279048 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. - |
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