Submissions for variant NM_000038.6(APC):c.1242C>T (p.Arg414=)

gnomAD frequency: 0.00004  dbSNP: rs751423790

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel	RCV003148671	SCV003836580	benign	Familial adenomatous polyposis 1	2023-02-18	reviewed by expert panel	curation	The c.1242C>T (p.Arg414=) variant in APC is a synonymous (silent) variant that is not predicted to impact splicing (BP4, BP7). This variant has been observed in heterozygous state in 11 healthy unrelated adult individuals worth 11 (more than 10) healthy individual points in total (BS2; Ambry internal data). While RT-PCR from internal data demonstrated no impact of the variant on splicing (Ambry Internal Data), transcription assays (not otherwise specified) in the literature demonstrated that the variant impacts splicing by leading to partial exon 10 skipping (p.V313_Q412del) (PMID 20685668). Functional evidence was disregarded in the classification of this variant as they showed conflicting results. The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.000034 (4/117512 alleles) in European (non-Finnish) population, which is higher than the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel (HCCP VCEP) threshold (0.00001) for BS1. In summary, this variant meets the criteria to be classified as Benign for FAP based on the ACMG/AMP criteria applied, as specified by the HCCP VCEP: BS1, BS2, BP4, and BP7 (VCEP specifications version 1; date of approval: 12/12/2022).
Labcorp Genetics (formerly Invitae), Labcorp	RCV003148671	SCV000252906	likely benign	Familial adenomatous polyposis 1	2023-12-18	criteria provided, single submitter	clinical testing
GeneDx	RCV001705141	SCV000518034	likely benign	not provided	2019-03-07	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 21901162, 20685668)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000441007	SCV000538292	likely benign	not specified	2016-06-23	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: Silent variant not near splice site. Reported in APC mutation spectrum paper.
Color Diagnostics, LLC DBA Color Health	RCV000579779	SCV000681449	likely benign	Hereditary cancer-predisposing syndrome	2017-05-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000579779	SCV001170714	likely benign	Hereditary cancer-predisposing syndrome	2018-03-29	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.
Sema4, Sema4	RCV000579779	SCV002533181	likely benign	Hereditary cancer-predisposing syndrome	2022-03-05	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002500619	SCV002813552	likely benign	Desmoid disease, hereditary; Familial adenomatous polyposis 1; Hepatocellular carcinoma; Gastric cancer; Colorectal cancer; Gastric adenocarcinoma and proximal polyposis of the stomach	2021-12-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001705141	SCV004219365	likely benign	not provided	2023-05-10	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996933	SCV004837372	likely benign	Classic or attenuated familial adenomatous polyposis	2024-07-29	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003148671	SCV004931804	benign	Familial adenomatous polyposis 1	2024-03-01	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.