Submissions for variant NM_000038.6(APC):c.313A>G (p.Ser105Gly)

gnomAD frequency: 0.00001  dbSNP: rs776242276

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000562645	SCV000667645	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-21	criteria provided, single submitter	clinical testing	The p.S105G variant (also known as c.313A>G), located in coding exon 3 of the APC gene, results from an A to G substitution at nucleotide position 313. The serine at codon 105 is replaced by glycine, an amino acid with similar properties. This alteration was identified in 1/103 individuals with colorectal cancer; however, clinical details were not provided for this individual (Chang YC et al. World J. Gastroenterol., 2016 Feb;22:2314-25). This amino acid position is highly conserved in available vertebrate species. In addition, in silico predictors for this gene do not accurately predict pathogenicity. Missense alterations in APC are not a common cause of disease (Spier I et al. Genet Med. 2024 Feb;26(2):100992). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV004561705	SCV000768101	uncertain significance	Familial adenomatous polyposis 1	2024-11-04	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 105 of the APC protein (p.Ser105Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with colon cancer (PMID: 37306523). ClinVar contains an entry for this variant (Variation ID: 482406). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt APC protein function with a negative predictive value of 95%. 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	RCV000562645	SCV000910987	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 105 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 26900293). This variant has not been identified 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.
GeneDx	RCV003441949	SCV004167731	uncertain significance	not provided	2023-10-04	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed in any cases, but was observed in unaffected controls from a biliary tract cancer study (Okawa et al., 2023); This variant is associated with the following publications: (PMID: 26900293, 36243179)
All of Us Research Program, National Institutes of Health	RCV004000984	SCV004837253	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-09-23	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 105 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 26900293). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD) but has been reported in a healthy control individual (PMID: 32980694). 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.
Baylor Genetics	RCV004561705	SCV005055998	uncertain significance	Familial adenomatous polyposis 1	2024-03-19	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV003441949	SCV005411834	uncertain significance	not provided	2024-08-19	criteria provided, single submitter	clinical testing	BP1, PM2
PreventionGenetics, part of Exact Sciences	RCV004740337	SCV005354728	uncertain significance	APC-related disorder	2024-03-07	no assertion criteria provided	clinical testing	The APC c.313A>G variant is predicted to result in the amino acid substitution p.Ser105Gly. This variant has been reported in a patient with colorectal cancer and in patient with biliary tract cancer, although conclusive evidence of pathogenicity was not provided (Chang et al. 2016. PubMed ID: 26900293; Table S2, Okawa et al. 2023. PubMed ID: 36243179). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/482406/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.