Submissions for variant NM_000038.6(APC):c.7574G>A (p.Arg2525His)

gnomAD frequency: 0.00006  dbSNP: rs762034315

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164075	SCV000214685	likely benign	Hereditary cancer-predisposing syndrome	2020-09-14	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226636	SCV000282826	likely benign	Familial adenomatous polyposis 1	2025-01-25	criteria provided, single submitter	clinical testing
Counsyl	RCV000226636	SCV000488429	uncertain significance	Familial adenomatous polyposis 1	2016-03-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000483633	SCV000567924	likely benign	not provided	2019-11-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27443514, 25479140, 29684080)
Color Diagnostics, LLC DBA Color Health	RCV000164075	SCV000681878	likely benign	Hereditary cancer-predisposing syndrome	2024-01-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483633	SCV001470120	likely benign	not provided	2019-11-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001582644	SCV001821417	likely benign	not specified	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: APC c.7574G>A (p.Arg2525His) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein basic domain (IPR009234) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 250814 control chromosomes. The observed variant frequency is approximately 2 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 benign. c.7574G>A has been reported in the literature as a VUS in settings of multigene cancer panel testing in affected individuals with cancers such as endometrial, hereditary breast and/or ovarian cancers (example, Ring_2016, Schubert_2019, Okawa_2023). These report(s) 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: 36243179, 27443514, 30426508). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (likely benign, n=5; VUS, n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000164075	SCV002528193	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-03	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000226636	SCV004017780	likely benign	Familial adenomatous polyposis 1	2023-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
All of Us Research Program, National Institutes of Health	RCV003995310	SCV004835696	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 2525 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 endometrial cancer (PMID: 27443514) and pancreatic cancer (PMID: 25479140, 32980694). This variant has also been identified in 40/282210 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy controls (PMID: 32980694). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV003995310	SCV005914443	uncertain significance	Classic or attenuated familial adenomatous polyposis	2019-10-24	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003937504	SCV004752575	likely benign	APC-related disorder	2022-09-13	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).