Submissions for variant NM_000038.6(APC):c.2876C>T (p.Ser959Phe)

gnomAD frequency: 0.00001  dbSNP: rs757526267

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003766563	SCV000552515	uncertain significance	Familial adenomatous polyposis 1	2024-07-16	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 959 of the APC protein (p.Ser959Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 28202063). ClinVar contains an entry for this variant (Variation ID: 411384). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758724	SCV000887512	uncertain significance	not provided	2018-05-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001016870	SCV001177871	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-06	criteria provided, single submitter	clinical testing	The p.S959F variant (also known as c.2876C>T), located in coding exon 15 of the APC gene, results from a C to T substitution at nucleotide position 2876. The serine at codon 959 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant, designated as c.C2876T, was reported in one individual from a cohort of 45 Lebanese breast cancer patients with personal and family histories of breast and/or ovarian cancer. Of note, it co-occured with a BRCA1 mutation ("c.G131T, p.C44F") in this individual (Jalkh N et al. BMC Med Genomics 2017 02;10:8). This amino acid position is well 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). Based on the available evidence, the clinical significance of this variant remains unclear.
GeneDx	RCV000758724	SCV001788586	uncertain significance	not provided	2024-12-06	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: 28202063)
Color Diagnostics, LLC DBA Color Health	RCV001016870	SCV002052736	uncertain significance	Hereditary cancer-predisposing syndrome	2025-03-17	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 959 of the APC protein. Computational prediction suggests that this variant may not impact protein structure and function. 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 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.
Sema4, Sema4	RCV001016870	SCV002530569	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-12	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004001929	SCV004839739	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 959 of the APC protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported to co-occur with BRCA1 p.Cys44Phe in an individual with a personal and family history of breast cancer (PMID: 28202063). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526679	SCV005039151	uncertain significance	not specified	2024-03-25	criteria provided, single submitter	clinical testing	Variant summary: APC c.2876C>T (p.Ser959Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250910 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2876C>T has been reported in the literature in one individual with a personal and family history of breast cancer (e.g. Jalkh_2017). However, the individual also possessed variants in BRCA1 (p.C44F) and PRF1 (p.M1I), with the BRCA1 variant being pathogenic, making the effect of the APC variant unclear for that tested phenotype. This report does 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. The following publication have been ascertained in the context of this evaluation (PMID: 28202063). ClinVar contains an entry for this variant (Variation ID: 411384). Based on the evidence outlined above, the variant was classified as uncertain significance.