ClinVar Miner

Submissions for variant NM_000038.6(APC):c.4261A>G (p.Ser1421Gly)

dbSNP: rs1303200783
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002526270 SCV000647507 uncertain significance Familial adenomatous polyposis 1 2023-10-20 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1421 of the APC protein (p.Ser1421Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 469958). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt APC protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health RCV000771645 SCV000904267 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV000771645 SCV001183871 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-21 criteria provided, single submitter clinical testing The p.S1421G variant (also known as c.4261A>G), located in coding exon 15 of the APC gene, results from an A to G substitution at nucleotide position 4261. The serine at codon 1421 is replaced by glycine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV001584308 SCV001819186 uncertain significance not provided 2023-01-17 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18199528)
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357116 SCV001552471 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The APC p.Ser1421Gly variant was not identified in the literature nor was it identified in the dbSNP, GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Clinvitae or Zhejiang Colon Cancer databases. The variant was identified in the ClinVar database as having uncertain significance by Invitae and listed 1X in the LOVD 3.0 database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, and the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The serine residue at amino acid 1421 is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of altering it; this information is insufficient to establish pathogenicity. The variant occurs outside of the splicing consensus sequence and although 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict that it could cause a greater than 10% difference in splicing, this is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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