Submissions for variant NM_000038.6(APC):c.7468G>A (p.Asp2490Asn)

gnomAD frequency: 0.00006  dbSNP: rs538230198

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000128974	SCV000172860	likely benign	Hereditary cancer-predisposing syndrome	2021-06-16	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Counsyl	RCV000409539	SCV000488075	uncertain significance	Familial adenomatous polyposis 1	2015-12-22	criteria provided, single submitter	clinical testing
Invitae	RCV003764862	SCV000552737	likely benign	Familial adenomatous polyposis 1	2024-01-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000656750	SCV000564583	uncertain significance	not provided	2023-06-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25980754, 28135145)
Color Diagnostics, LLC DBA Color Health	RCV000128974	SCV000681867	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-15	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 2490 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 colorectal cancer who also carried a pathogenic MLH1 c.1989+3dupC variant that could explain the observed cancer (PMID: 25980754, 28135145). This variant has been identified in 14/282640 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	RCV000656750	SCV001133367	uncertain significance	not provided	2019-07-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731385	SCV001983664	uncertain significance	not specified	2021-09-16	criteria provided, single submitter	clinical testing	Variant summary: APC c.7468G>A (p.Asp2490Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251252 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.54 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.7468G>A has been reported in the literature in individuals affected with colorectal cancer and suspected Lynch syndrome (Yurgelun_2015, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis.The variant has been reported in a patient along with a different pathogenic APC mutation (Invitae internal data, via ClinVar), however additional information was not provided. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 a VUS.
Sema4, Sema4	RCV000128974	SCV002527656	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-10	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000409539	SCV004018770	uncertain significance	Familial adenomatous polyposis 1	2023-02-21	criteria provided, single submitter	clinical testing	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.
PreventionGenetics, part of Exact Sciences	RCV003407537	SCV004109820	uncertain significance	APC-related condition	2022-09-01	criteria provided, single submitter	clinical testing	The APC c.7468G>A variant is predicted to result in the amino acid substitution p.Asp2490Asn. This variant was reported as a variant of uncertain significance in an individual with colorectal cancer and another individual undergoing Lynch syndrome panel testing (Supp. Table 2 in Yurgelun MB et al 2015. PubMed ID: 25980754; Table A4. in Yurgelun et al 2017. PubMed ID: 28135145). This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-112178759-G-A) and as uncertain in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/140800). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000481415	SCV000591208	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC, p.Asp2490Asn variant was identified in dbSNP (ID: rs538230198) as “With uncertain significance allele”, Clinvitae database (uncertain significance), and ClinVar database (uncertain significance, Ambry Genetics). The variant was not found in the COSMIC, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), GeneInsight - COGR database, or UMD. This variant was identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004) and in the Exome Aggregation Consortium database (March 14 2016) in 5 of 66714 chromosomes (frequency: 0.0007) 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.Asp2490 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 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. This variant is classified as a variant of uncertain significance.