Submissions for variant NM_000038.6(APC):c.7717A>G (p.Ile2573Val)

gnomAD frequency: 0.00007  dbSNP: rs145444830

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003650359	SCV000166060	likely benign	Familial adenomatous polyposis 1	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000163980	SCV000214580	likely benign	Hereditary cancer-predisposing syndrome	2018-09-20	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	RCV000034421	SCV000292853	likely benign	not provided	2021-01-21	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27600092, 22703879, 21859464, 25637381, 22975805, 18199528, 31159747)
Counsyl	RCV000122803	SCV000489022	uncertain significance	Familial adenomatous polyposis 1	2016-08-05	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000236063	SCV000538305	uncertain significance	not specified	2017-01-24	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 2 individuals with colorectal adenomas and 1 individual with no cancer. The variant has a Max MAF of 0.03% in ExAC (18 alleles) and 0.02% in gnomAD (21 alleles). Frequency too high for disease? It is classified with 2 stars in ClinVar as VUS by Invitae, Ambry, GeneDx, CSER_CC_NCGL, and Biesecker lab. 10 non-mammals have a Val at this position.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034421	SCV000600159	uncertain significance	not provided	2019-11-08	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000034421	SCV000805470	uncertain significance	not provided	2018-01-02	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000163980	SCV000821826	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000163980	SCV000910847	likely benign	Hereditary cancer-predisposing syndrome	2016-06-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163980	SCV002530799	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-13	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236063	SCV002550663	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000122803	SCV004018795	likely benign	Familial adenomatous polyposis 1	2023-02-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236063	SCV004099683	likely benign	not specified	2023-09-11	criteria provided, single submitter	clinical testing	Variant summary: APC c.7717A>G (p.Ile2573Val) 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 8.8e-05 in 250818 control chromosomes, predominantly at a frequency of 0.00018 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 2.5 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 Non-Finnish European origin. c.7717A>G has been reported in the literature in and individual affected with Colorectal Adenomas (Azzopard_2008) without evidence for causality. This report does 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 publication have been ascertained in the context of this evaluation (PMID: 18199528). Twelve submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as likely benign (n=6) and VUS (n=6). Based on the evidence outlined above, the variant was classified as likely benign.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034421	SCV000043140	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
CSER _CC_NCGL, University of Washington	RCV000148373	SCV000190067	uncertain significance	Colorectal adenoma	2014-06-01	no assertion criteria provided	research