Submissions for variant NM_000038.6(APC):c.7415C>T (p.Ala2472Val)

gnomAD frequency: 0.00003  dbSNP: rs200399245

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122799	SCV000166056	likely benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000164132	SCV000214747	likely benign	Hereditary cancer-predisposing syndrome	2021-08-13	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.
GeneDx	RCV000034398	SCV000293281	uncertain significance	not provided	2018-05-21	criteria provided, single submitter	clinical testing	This variant is denoted APC c.7415C>T at the cDNA level, p.Ala2472Val (A2472V) at the protein level, and results in the change of an Alanine to a Valine (GCT>GTT). APC Ala2472Val has been reported in a patient with colorectal cancer (Yurgelun 2017), in two patients with breast and/or ovarian cancer (Maxwell 2016), and in two individuals with no specific information provided regarding cancer history (Johnston 2012, Rodriguez-Flores 2014). APC Ala2472Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). APC Ala2472Val is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether APC Ala2472Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Illumina Laboratory Services, Illumina	RCV000408370	SCV000452045	likely benign	APC-Associated Polyposis Disorders	2016-06-14	criteria provided, single submitter	clinical testing
Counsyl	RCV000122799	SCV000488669	uncertain significance	Familial adenomatous polyposis 1	2016-05-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000235447	SCV000593261	uncertain significance	not specified	2016-08-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034398	SCV000600147	uncertain significance	not provided	2023-07-07	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals and families affected with breast cancer (PMIDs: 27153395 (2016), 25186627 (2015)), colorectal cancer (PMID: 28135145 (2017)), and unaffected individuals (PMIDs: 24123366 (2014), 22703879 (2012)). The frequency of this variant in the general population, 0.00011 (4/35406 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools or the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000164132	SCV000681865	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-25	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 2472 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 individuals affected with colorectal cancer (PMID: 28135145) and breast/ovarian cancer (PMID: 25186627 , 27153395; DOI: 10.1101/2021.04.15.21255554v2) in the literature, but has also been observed in populations not selected for cancer (PMID: 22703879, 24123366). The variant has also been observed to co-occur with an APC truncation in the NA11410 colorectal cancer cell line. This variant has been identified in 11/282564 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034398	SCV000883408	uncertain significance	not provided	2018-03-29	criteria provided, single submitter	clinical testing	The APC c.7415C>T; p.Ala2472Val variant (rs200399245) is reported in the medical literature in two individuals with breast cancer (Maxwell 2016) and in one individual with colorectal cancer (Yurgelun 2016). However, the variant is also described in individuals not selected for a personal or family history of cancer (Johnston 2012, Rodriguez-Flores 2014). The variant is reported in the ClinVar database (Variation ID: 41513). The variant is also listed in the Genome Aggregation Database in 9/276906 alleles. The alanine at this position is weakly conserved across species and computational algorithms (PolyPhen-2, SIFT) predict this variant is tolerated. Considering available information, there is insufficient evidence to classify this variant with certainty. However, the vast majority of pathogenic APC variants are truncating nonsense or frameshift variants (see InSiGHt, Kerr 2013). Pathogenic APC variants are causative for adenomatous polyposis coli (MIM: 175100). References: Link to InSiGHt: https://www.insight-group.org/syndromes/adenomatous-polyposis/ Johnston JJ et al. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet. 2012 Jul 13;91(1):97-108. Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31-43. Maxwell KN et al. Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer. Am J Hum Genet. 2016 May 5;98(5):801-817. Rodriguez-Flores JL et al. Exome sequencing identifies potential risk variants for Mendelian disorders at high prevalence in Qatar. Hum Mutat. 2014 Jan;35(1):105-16. Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235447	SCV001337711	likely benign	not specified	2020-10-29	criteria provided, single submitter	clinical testing	Variant summary: APC c.7415C>T (p.Ala2472Val) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 143306 control chromosomes, predominantly at a frequency of 0.0013 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 18 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.7415C>T has been reported in the literature in an individual affected with colorectal cancer (Yurgelun_2017) and individuals with breast cancer (Tung_2015) without strong evidence for causality. These reports 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. Nine ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (6x) and likely benign (3x). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000164132	SCV002527612	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-20	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV002228086	SCV004018837	uncertain significance	Familial adenomatous polyposis 1	2023-02-23	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.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034398	SCV000043138	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.