Submissions for variant NM_000038.6(APC):c.1290C>T (p.Gly430=)

gnomAD frequency: 0.00001  dbSNP: rs730881234

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159531	SCV000209491	uncertain significance	not provided	2023-12-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV000567240	SCV000667394	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-23	criteria provided, single submitter	clinical testing	The c.1290C>T variant (also known as p.G430G), located in coding exon 9 of the APC gene, results from a C to T substitution at nucleotide position 1290. This nucleotide substitution does not change the glycine at codon 430. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of 9 amino acids; however, the exact functional impact of the deleted amino acids is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516408	SCV000953298	uncertain significance	Familial adenomatous polyposis 1	2024-11-27	criteria provided, single submitter	clinical testing	This sequence change affects codon 430 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 likely results in the loss of 9 and insertion of 1 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs730881234, gnomAD 0.007%). 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: 181786). Studies have shown that this variant results in the activation of a cryptic splice site in exon 9 (internal data). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114307	SCV003800664	uncertain significance	not specified	2023-01-16	criteria provided, single submitter	clinical testing	Variant summary: APC c.1290C>T alters a non-conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: 4 predict the variant creates/strengthens a cryptic 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 250774 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1290C>T in individuals affected with Familial Adenomatous Polyposis and no experimental evidence demonstrating its impact on protein function have been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003998403	SCV004837376	uncertain significance	Classic or attenuated familial adenomatous polyposis	2023-05-04	criteria provided, single submitter	clinical testing	This synonymous variant causes a nucleotide substitution but does not change the encoded amino acid at codon 430 of the APC protein. Splice site prediction tools suggest that this variant may impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 2/250774 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159531	SCV005623639	uncertain significance	not provided	2024-07-11	criteria provided, single submitter	clinical testing	The APC c.1290C>T (p.Gly430=) synonymous variant has not been reported in individuals with APC-related conditions in the published literature. The frequency of this variant in the general population, 0.000008 (2/250774 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on APC mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Based on the available information, we are unable to determine the clinical significance of this variant.