Submissions for variant NM_000038.6(APC):c.449A>G (p.Lys150Arg)

gnomAD frequency: 0.00004  dbSNP: rs371085910

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130643	SCV000185522	likely benign	Hereditary cancer-predisposing syndrome	2021-04-10	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000656744	SCV000209566	uncertain significance	not provided	2022-12-18	criteria provided, single submitter	clinical testing	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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206082	SCV000260480	uncertain significance	Familial adenomatous polyposis 1	2025-02-02	criteria provided, single submitter	clinical testing	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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 (internal data). 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.
Color Diagnostics, LLC DBA Color Health	RCV000130643	SCV000686977	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000211892	SCV000711457	uncertain significance	not specified	2020-05-22	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Counsyl	RCV000206082	SCV000785842	uncertain significance	Familial adenomatous polyposis 1	2017-12-18	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000206082	SCV000890906	uncertain significance	Familial adenomatous polyposis 1	2021-08-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211892	SCV000918433	uncertain significance	not specified	2018-03-23	criteria provided, single submitter	clinical testing	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.
Sema4, Sema4	RCV000130643	SCV002534305	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211892	SCV002550563	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000206082	SCV004018476	likely benign	Familial adenomatous polyposis 1	2023-02-17	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000206082	SCV004200933	uncertain significance	Familial adenomatous polyposis 1	2024-03-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998072	SCV004837273	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-08-06	criteria provided, single submitter	clinical testing	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656744	SCV005624499	uncertain significance	not provided	2024-08-15	criteria provided, single submitter	clinical testing	The APC c.449A>G (p.Lys150Arg) variant has been reported in the published literature in individuals affected with colorectal adenomas (PMIDs: 18199528 (2008), 21859464 (2011)), early-onset breast cancer (PMID: 28503720 (2017)), and pediatric sarcomas (PMIDs: 26580448 (2015), 34301788 (2021)). The frequency of this variant in the general population, 0.000031 (4/127816 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
CSER _CC_NCGL, University of Washington	RCV000148370	SCV000190062	uncertain significance	Colorectal adenoma	2014-06-01	no assertion criteria provided	research
True Health Diagnostics	RCV000130643	SCV000693483	uncertain significance	Hereditary cancer-predisposing syndrome	2017-09-25	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739446	SCV000805411	uncertain significance	APC-related disorder	2024-04-17	no assertion criteria provided	clinical testing	The APC c.449A>G variant is predicted to result in the amino acid substitution p.Lys150Arg. This variant has been reported in individuals with colorectal adenoma (Azzopardi et al. 2008. PubMed ID: 18199528; Table S1, Minde. 2011. PubMed ID: 21859464 ) and in a patient with invasive early-onset breast cancer (Rummel et al. 2017. PubMed ID: 28503720). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is listed in ClinVar as likely benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/141928/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.