ClinVar Miner

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

gnomAD frequency: 0.00004  dbSNP: rs751423790
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Total submissions: 9
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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).
Invitae 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: 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

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