ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1956C>T (p.His652=)

dbSNP: rs1064793716
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel RCV002525790 SCV003836592 likely pathogenic Familial adenomatous polyposis 1 2023-02-25 reviewed by expert panel curation The c.1956C>T variant in APC is predicted to be a synonymous (silent) variant (p.His652=). It is located at the third-last nucleotide of exon 15. Two RNA based RT-PCR assays demonstrate out-of-frame skipping of exon 15, with evidence that the variant allele produces <10% of the full-length transcript (PS3; PMID: 15459959, 22987206). This variant has been reported in 3 probands meeting least 1.5 phenotype points (PS4_Supporting; PMID: 15459959, 22987206). The variant is not reported in gnomAD (PM2_supporting). In summary, this variant meets the criteria to be classified as Likely Pathogenic for FAP based on the ACMG/AMP criteria applied, as specified by the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation Expert Panel: PS3, PS4_Supporting and PM2_Supporting (VCEP specifications version 1; date of approval: 12/12/2022).
GeneDx RCV000482661 SCV000566856 likely pathogenic not provided 2018-04-09 criteria provided, single submitter clinical testing This variant is denoted APC c.1956C>T at the DNA level. Although the variant is a synonymous substitution at the coding level, preserving a Histidine at codon 652, it has been demonstrated to cause exon skipping by RNA analysis (Aretz 2004, Schwarzová 2013). APC c.1956C>T was not observed in large population cohorts (Lek 2016).This variant has been observed in individuals with classic and attenuated familial adenomatous polyposis and has shown segregation with disease in internal cases, in the literature, and by another clinical laboratory (Aretz 2004, Friedl 2005, Schwarzová 2013, SCV000647207.1). Based on currently available evidence, we consider APC c.1956C>T to be a likely pathogenic variant.
Invitae RCV003743733 SCV000647207 pathogenic Familial adenomatous polyposis 1 2023-11-27 criteria provided, single submitter clinical testing This sequence change affects codon 652 of the APC mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the APC protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with familial adenomatous polyposis (FAP) (PMID: 15459959, 22987206; Invitae). ClinVar contains an entry for this variant (Variation ID: 419202). Studies have shown that this variant results in skipping of exon 15 (also called exon 14) and introduces a premature termination codon (PMID: 15459959, 22987206; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001013836 SCV001174471 pathogenic Hereditary cancer-predisposing syndrome 2021-12-28 criteria provided, single submitter clinical testing The c.1956C>T pathogenic variant (also known as p.H652H), located in coding exon 14 of the APC gene, results from a C to T substitution at nucleotide position 1956. This nucleotide substitution does not change the residue at codon 652. This alteration has been reported in multiple individuals with familial adenomatous polyposis (Ambry internal data; Aretz S et al. Hum. Mutat. 2004 Nov;24(5):370-80; Schwarzov&aacute; L et al. Fam. Cancer 2013 Mar;12(1):35-42). This nucleotide position is highly conserved in available vertebrate species. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis for this alteration is inconclusive. However, multiple RNA analyses have shown that this alteration leads to substantial exon 14 skipping (Ambry internal data; Aretz S et al. 2004; Schwarzov&aacute; L et al. 2013). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation..
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000502897 SCV000591098 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The APC p.His652His variant was identified in 2 of 2512 proband chromosomes (frequency: 0.001) from German and Czech individuals or families with FAP/AFAP (Friedl 2005, Schwarzova 2013). Aretz et al (2004) were first to show this silent variant resulted in exon 14 skipping similar to substitutions at highly conserved splice acceptor and donor sites, versus the alternative splicing nature of exon 14 seen in normal controls, which was contrary to calls made by splice prediction models. This finding was also seen by Schwarzova (2013), in a patient with AFAP, who by RNA based RT-PCR analysis was shown to have the same or higher amounts of the mutant transcript in his blood, healthy colon and polyp tissue, compared to the blood and colon mucosa of healthy individuals. The variant was not identified in dbSNP, 1000 Genomes Project, NHLBI GO Exome Sequencing Project , the Exome Aggregation Consortium database, Clinvitae database, Zhejiang Colon Cancer Database (LOVD), ClinVar database, GeneInsight - COGR database, and UMD; but was identified in COSMIC (1x in an adenomacarcinoma of the large intestine, with somatic status) and in InSiGHT Colon Cancer Gene Variant Database (LOVD) (2x as a pathogenic germline mutation, in a classical FAP phenotype, and one unknown phenotype). The c.1956C>T variant occurs in the third last base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. Two of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a difference in splicing and functional studies have demonstrated a splicing defect contradicting, increasing the likelihood this variant has clinical significance. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.