Submissions for variant NM_000038.6(APC):c.775C>T (p.Arg259Trp)

gnomAD frequency: 0.00001  dbSNP: rs762117133

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV003743727	SCV000552762	uncertain significance	Familial adenomatous polyposis 1	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 259 of the APC protein (p.Arg259Trp). This variant is present in population databases (rs762117133, gnomAD 0.007%). This missense change has been observed in individual(s) with biliary tract cancer (PMID: 36243179). ClinVar contains an entry for this variant (Variation ID: 411556). 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.
Ambry Genetics	RCV000572577	SCV000676367	likely benign	Hereditary cancer-predisposing syndrome	2021-05-14	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Color Diagnostics, LLC DBA Color Health	RCV000572577	SCV000681886	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 259 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 sarcoma (PMID: 31702654). However, case-control studies reported no significant association with colorectal cancer or pancreatic cancer (PMID: 33309985, 32980694). This variant has been identified in 6/251012 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.
Counsyl	RCV000465724	SCV000786061	uncertain significance	Familial adenomatous polyposis 1	2018-02-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779741	SCV000916515	uncertain significance	not specified	2021-11-09	criteria provided, single submitter	clinical testing	Variant summary: APC c.775C>T (p.Arg259Trp) 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 allele was found at a frequency of 2.4e-05 in 251012 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.775C>T has been reported in the literature in individuals affected with Familial Adenomatous Polyposis. 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. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001357050	SCV002011083	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000465724	SCV004015161	uncertain significance	Familial adenomatous polyposis 1	2023-07-07	criteria provided, single submitter	clinical testing	the sequence change replaces arginine with tryptophan at codon 259 of the APC protein (p.Arg259Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs762117133, ExAC 0.01%). This variant has not been reported in the literature in individuals with APC-related disease. ClinVar contains an entry for this variant (Variation ID: 411556). In-silico simulator software to predict the effect of missense changes on protein structure and function showed (SIFT: "Deleterious"; PolyPhen-2: "benign"). Therefore, it has been classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc.	RCV000465724	SCV004018319	uncertain significance	Familial adenomatous polyposis 1	2023-02-14	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.
True Health Diagnostics	RCV000572577	SCV000693494	uncertain significance	Hereditary cancer-predisposing syndrome	2017-10-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357050	SCV001552379	uncertain significance	not provided		no assertion criteria provided	clinical testing	The APC p.R259W variant was identified in the literature from one infant with Ewing-like sarcoma/undifferentiated round cell sarcoma who also had additional variants of uncertain significance in MSH6 (p.P1082S) and KMT2D (p.K2548E) (Xiong_2019_PMID:31702654). The variant was identified in dbSNP (ID: rs762117133), Cosmic and ClinVar (classified as uncertain significance by Counsyl, Invitae, Ambry Genetics, Color, True Health Diagnostics and Integrated Genetics). The variant was identified in control databases in 5 of 236492 chromosomes at a frequency of 0.00002114 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: South Asian in 2 of 30494 chromosomes (freq: 0.000066), East Asian in 1 of 17642 chromosomes (freq: 0.000057) and European (non-Finnish) in 2 of 102476 chromosomes (freq: 0.00002), but was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), or Other populations. The p.R259 residue is conserved in mammals and computational analyses (PolyPhen-2, MutationTaster, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.