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

gnomAD frequency: 0.00001  dbSNP: rs757526267

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003766563	SCV000552515	uncertain significance	Familial adenomatous polyposis 1	2024-01-07	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	2022-07-15	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, 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.
GeneDx	RCV000758724	SCV001788586	uncertain significance	not provided	2020-12-07	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports 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	2023-01-18	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.
Sema4, Sema4	RCV001016870	SCV002530569	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-12	criteria provided, single submitter	curation