Submissions for variant NM_000038.6(APC):c.2090C>T (p.Ala697Val)

gnomAD frequency: 0.00003  dbSNP: rs761733547

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200684	SCV000253993	benign	Familial adenomatous polyposis 1	2025-01-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000200684	SCV000488186	uncertain significance	Familial adenomatous polyposis 1	2016-01-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000657015	SCV000566393	uncertain significance	not provided	2024-07-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including kidney cancer and osteosarcoma in published literature (PMID: 26580448, 29684080); This variant is associated with the following publications: (PMID: 27149842, 24755471, 29684080, 26580448, 18199528)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484738	SCV000600055	uncertain significance	not specified	2017-07-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575021	SCV000667304	likely benign	Hereditary cancer-predisposing syndrome	2021-05-19	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.
Color Diagnostics, LLC DBA Color Health	RCV000575021	SCV000686875	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 697 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 not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 1/250802 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000484738	SCV001362435	uncertain significance	not specified	2023-08-28	criteria provided, single submitter	clinical testing	Variant summary: APC c.2090C>T (p.Ala697Val) results in a non-conservative amino acid change located in the Armadillo domain of 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 4e-06 in 250802 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2090C>T has been reported in the literature (Giannakis_2016, Zhang_2015). 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. The following publications have been ascertained in the context of this evaluation (PMID: 26580448, 27760322). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=7) and benign/likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000575021	SCV002529842	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-27	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000200684	SCV002584713	uncertain significance	Familial adenomatous polyposis 1	2022-10-07	criteria provided, single submitter	clinical testing	The APC c.2090C>T (p.Ala697Val) missense change has a maximum subpopulation frequency of 0.0062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with APC-related familial adenomatous polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Myriad Genetics, Inc.	RCV000200684	SCV004017880	uncertain significance	Familial adenomatous polyposis 1	2023-02-16	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.
Baylor Genetics	RCV000200684	SCV004201333	uncertain significance	Familial adenomatous polyposis 1	2023-08-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996966	SCV004839641	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with valine at codon 697 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 individuals affected with kidney cancer, osteosarcoma, or colorectal cancer (24755471, 26580448, 29684080). This variant has been identified in 1/250802 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	RCV000657015	SCV005876758	uncertain significance	not provided	2024-06-18	criteria provided, single submitter	clinical testing	The APC c.2090C>T; p.Ala697Val variant (rs761733547, ClinVar Variation ID: 216153) has been reported in the literature as a germline variant identified in a patient with osteosarcoma; however, the variant was not determined to be causative (Zhang 2015). This variant is only found on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.289). The vast majority of pathogenic APC variants are truncating nonsense or frameshift variants (see InSiGHt, Kerr 2013). Due to limited information, the clinical significance of this missense variant is uncertain at this time. References: Link to InSiGHt: https://www.insight-group.org/syndromes/adenomatous-polyposis/. 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. PMID: 23159591. Zhang J et al. Germline Mutations in Predisposition Genes in Pediatric Cancer. N Engl J Med. 2015 Dec 10;373(24):2336-2346. PMID: 26580448.