Submissions for variant NM_000038.6(APC):c.1243G>A (p.Ala415Thr)

gnomAD frequency: 0.00001  dbSNP: rs756336949

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003534474	SCV000552596	uncertain significance	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 415 of the APC protein (p.Ala415Thr). This variant is present in population databases (rs756336949, gnomAD 0.009%). This missense change has been observed in individual(s) with endometrial cancer and colon cancer (PMID: 27443514, 27978560). ClinVar contains an entry for this variant (Variation ID: 217920). 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 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.
GeneDx	RCV000657057	SCV000567891	uncertain significance	not provided	2023-10-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27443514, 27978560, 25980754)
Ambry Genetics	RCV000571880	SCV000667283	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-08	criteria provided, single submitter	clinical testing	The p.A415T variant (also known as c.1243G>A), located in coding exon 9 of the APC gene, results from a G to A substitution at nucleotide position 1243. The alanine at codon 415 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in a female patient with a mismatch repair proficient sigmoid colorectal cancer at age 47 (Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). It has also been reported in a cohort of 381 endometrial carcinoma patients who had undergone tumor testing to screen for Lynch syndrome (Ring KL et al. Mod. Pathol. 2016 Nov;29:1381-1389). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000571880	SCV000911386	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-23	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 415 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 early-onset colorectal cancer (PMID: 27978560). This variant has been identified in 5/250582 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.
Mendelics	RCV000466853	SCV001136882	uncertain significance	Familial adenomatous polyposis 1	2019-05-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000202029	SCV002066657	uncertain significance	not specified	2020-11-03	criteria provided, single submitter	clinical testing	DNA sequence analysis of the APC gene demonstrated a sequence change, c.1243G>A, in exon 10 that results in an amino acid change, p.Ala415Thr. This sequence change has been described in the gnomAD database in five individuals with an overall population frequency of 0.002% (dbSNP rs756336949). The p.Ala415Thr change has been reported in individuals with endometrial cancer and colon cancer (PMIDs: 27443514, 27978560). The p.Ala415Thr change affects a highly conserved amino acid residue located in a domain of the APC protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Ala415Thr substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ala415Thr change remains unknown at this time.
Sema4, Sema4	RCV000571880	SCV002533292	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-21	criteria provided, single submitter	curation
Baylor Genetics	RCV000466853	SCV004198159	uncertain significance	Familial adenomatous polyposis 1	2023-10-16	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202029	SCV000256912	uncertain significance	not specified		no assertion criteria provided	research