Submissions for variant NM_000038.6(APC):c.262C>T (p.Arg88Trp)

gnomAD frequency: 0.00001  dbSNP: rs746592911

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766533	SCV000569765	uncertain significance	not provided	2023-01-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Yehia et al., 2018); This variant is associated with the following publications: (PMID: 24463508, 29684080, 10830991)
Ambry Genetics	RCV000574492	SCV000667444	likely benign	Hereditary cancer-predisposing syndrome	2021-06-11	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	RCV000574492	SCV000681542	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 88 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 in an individual affected with familial adenomatous polyposis, however it co-occurred with truncating variant in the APC gene (PMID: 10830991). This variant has been identified in 12/282816 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.
Invitae	RCV003651926	SCV000768216	uncertain significance	Familial adenomatous polyposis 1	2024-01-28	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 88 of the APC protein (p.Arg88Trp). This variant is present in population databases (rs746592911, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with APC-related conditions. ClinVar contains an entry for this variant (Variation ID: 420793). 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.
Mendelics	RCV000646444	SCV000838058	uncertain significance	Familial adenomatous polyposis 1	2018-07-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000766533	SCV002062606	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000574492	SCV002536808	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-03	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282167	SCV002571843	uncertain significance	not specified	2022-08-01	criteria provided, single submitter	clinical testing	Variant summary: APC c.262C>T (p.Arg88Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251438 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.262C>T has been reported in the literature in a proband affected with Familial Adenomatous Polyposis but was not found to segregate with disease in at least one other affected family member. Following further testing, a known pathogenic variant (p.Arg213X) was identified in both, the proband and the affected relative, indicating this to be the causative genetic factor of FAP in this family (Ogiso_2000). However, a ClinVar submitter reports identification of the variant in their laboratory in a family with polyposis, co-segregating with disease in 2 sisters (SCV000591021.2). These reports 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. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000484135	SCV000591021	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The APC p.Arg88Trp variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (rs746592911) as “with uncertain significance allele”, ClinVar (interpreted as "uncertain significance" by Invitae and 5 others) and LOVD 3.0 (observed 1x). The variant was identified in control databases in 12 of 277,172 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24,030 chromosomes (freq: 0.00004), Other in 1 of 6464 chromosomes (freq: 0.0002), Latino in 1 of 34,414 chromosomes (freq: 0.00003), European in 6 of 126,686 chromosomes (freq: 0.00005), Finnish in 3 of 25786 chromosomes (freq: 0.0001); it was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The variant has previously been identified in our laboratory in a family with polyposis, it co-segregated with 2 sisters affected with polyposis. The p.Arg88 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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.