Submissions for variant NM_000038.6(APC):c.4395T>A (p.Ser1465Arg)

gnomAD frequency: 0.00004  dbSNP: rs779898882

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198718	SCV000254015	likely benign	Familial adenomatous polyposis 1	2025-01-23	criteria provided, single submitter	clinical testing
GeneDx	RCV000766728	SCV000293401	uncertain significance	not provided	2025-01-31	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27194209, 21859464, 26336887, 18369740, 30306255, 25742471, 26862949, 18199528)
Color Diagnostics, LLC DBA Color Health	RCV000446409	SCV000537583	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 1465 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 not been reported in individuals affected with APC-related disorders in the literature. This variant has been identified in 4/251176 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.
Ambry Genetics	RCV000446409	SCV000579788	likely benign	Hereditary cancer-predisposing syndrome	2020-09-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236990	SCV000600100	uncertain significance	not specified	2017-05-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000198718	SCV000784952	uncertain significance	Familial adenomatous polyposis 1	2017-02-16	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000236990	SCV001478762	uncertain significance	not specified	2021-01-30	criteria provided, single submitter	clinical testing	Variant summary: APC c.4395T>A (p.Ser1465Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251176 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4395T>A has been reported in the literature in individuals affected with breast cancer but not in the setting of familial adenomatous polyposis (example, Gurda_2017, Bonache_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=4), some citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000766728	SCV002050070	uncertain significance	not provided	2020-11-14	criteria provided, single submitter	clinical testing	The APC c.4395T>A; p.Ser1465Arg variant (rs779898882) has been published in the germline of at least one individual undergoing multi-gene cancer testing (Wong 2015). The variant is reported in the ClinVar database (Variation ID: 216164) and is found in the European (non-Finnish) population with an allele frequency of 0.004% (4/113,506 alleles) in the Genome Aggregation Database. The serine at codon 1465 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.175). However, the vast majority of pathogenic APC variants are truncating nonsense or frameshift variants (see InSiGHt, Kerr 2013). Due to limited information, the clinical significance of the p.Ser1465Arg variant is uncertain at this time. References: Link to InSiGHt: https://www.insight-group.org/syndromes/adenomatous-polyposis/. Kerr SE et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013 Jan;15(1):31-43. Wong SQ et al. Assessing the clinical value of targeted massively parallel sequencing in a longitudinal, prospective population-based study of cancer patients. Br J Cancer. 2015 Apr 14;112(8):1411-20.
Genetic Services Laboratory, University of Chicago	RCV000236990	SCV002071948	uncertain significance	not specified	2021-10-19	criteria provided, single submitter	clinical testing	DNA sequence analysis of the APC gene demonstrated a sequence change, c.4395T>A, in exon 16 that results in an amino acid change, p.Ser1465Arg. This sequence change has been described in the gnomAD database with a frequency of 0.004% in the non-Finnish European subpopulation (dbSNP rs779898882). The p.Ser1465Arg change affects a moderately conserved amino acid residue located in a domain of the APC protein that is not known to be functional. The p.Ser1465Arg substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been previously reported in an individual with clear cell renal cell carcinoma (PMID: 25742471). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Ser1465Arg change remains unknown at this time.
Sema4, Sema4	RCV000446409	SCV002532060	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-02	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000198718	SCV004018966	uncertain significance	Familial adenomatous polyposis 1	2023-02-15	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV003996975	SCV004837927	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-08-30	criteria provided, single submitter	clinical testing	This missense variant replaces serine with arginine at codon 1465 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with an unspecified cancer (PMID: 25742471). This variant has been identified in 4/251176 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.