Submissions for variant NM_000038.6(APC):c.4918C>T (p.Arg1640Trp)

gnomAD frequency: 0.00010  dbSNP: rs373440614

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131255	SCV000186218	benign	Hereditary cancer-predisposing syndrome	2021-03-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
GeneDx	RCV000587871	SCV000209528	uncertain significance	not provided	2022-11-02	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer, thrombocytopenia, and features of Familial Adenomatous Polyposis (Scott et al., 2004; Penkert et al., 2018; Kewan et al., 2020); This variant is associated with the following publications: (PMID: 25637381, 21859464, 24055113, 20233475, 7833931, 27150160, 30086788, 32618208, 34426522, 18199528)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000148368	SCV000282767	uncertain significance	Familial adenomatous polyposis 1	2024-01-29	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 1640 of the APC protein (p.Arg1640Trp). This variant is present in population databases (rs373440614, gnomAD 0.01%). This missense change has been observed in individual(s) with familial adenomatous polyposis (FAP) (PMID: 7833931, 20233475). It has also been observed to segregate with disease in related individuals. This variant is also known as 4921C>T, Arg1841Trp. ClinVar contains an entry for this variant (Variation ID: 142246). 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.
Color Diagnostics, LLC DBA Color Health	RCV000131255	SCV000681696	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1640 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 individuals affected with familial adenomatous polyposis (PMID: 11317365, 20233475, 7833931, 8888441), an individual affected with breast cancer (PMID: 29684080), an individual affected with a serous gynecological cancer (PMID: 27150160). This variant has also been identified in 22/282560 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy control individuals (PMID: 32980694). 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	RCV001175337	SCV000694064	uncertain significance	not specified	2019-11-13	criteria provided, single submitter	clinical testing	Variant summary: APC c.4918C>T (p.Arg1640Trp) results in a non-conservative amino acid change located in the Adenomatous polyposis coli protein repeat (IPR009223) of 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 8.4e-05 in 251366 control chromosomes, predominantly at a frequency of 0.00017 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), suggesting that the variant is in the benign spectrum. c.4918C>T has been reported in the literature in individuals affected with Li-Fraumeni(-like) breast cancer and Familial Adenomatous Polyposis (Penkert_2018, Scott_2004). Additionally, the variant was shown to segregate with disease (FAP) in a small family study (Stella_1994). However the possibility of co-incidental co-segregation cannot be ruled out. The testing was a PCR-based SSCP screening approach. These data indicate that the variant may be associated with disease. Co-occurrence with a likely pathogenic variant has been reported (ATM c.2192dupA, p.Tyr731X; Internal sample). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587871	SCV000887527	uncertain significance	not provided	2017-09-06	criteria provided, single submitter	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000148368	SCV002012428	uncertain significance	Familial adenomatous polyposis 1	2021-10-12	criteria provided, single submitter	clinical testing	The APC c.4918C>T (p.Arg1640Trp) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/5-112176209-C-T?dataset=gnomad_r2_1). This variant has been reported in individuals with familial adenomatous polyposis (PMID: 7833931, 20233475) and has been found to segregate with disease in affected family members (PMID: 20233475). It has also been reported in an individual with a personal and/or family history suggestive of Li-Fraumeni syndrome who did not harbor pathogenic germline variants in BRCA1/2, or TP53 (PMID: 30086788). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: no criteria met.
Genetic Services Laboratory, University of Chicago	RCV001175337	SCV002067198	uncertain significance	not specified	2018-07-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131255	SCV002534898	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-14	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001175337	SCV002760358	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000148368	SCV004202160	uncertain significance	Familial adenomatous polyposis 1	2023-08-13	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003998094	SCV004837983	uncertain significance	Classic or attenuated familial adenomatous polyposis	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 1640 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 individuals affected with familial adenomatous polyposis (PMID: 11317365, 20233475, 7833931, 8888441), an individual affected with breast cancer (PMID: 29684080), an individual affected with a serous gynecological cancer (PMID: 27150160). This variant has also been identified in 22/282560 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in healthy control individuals (PMID: 32980694). 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.
CSER _CC_NCGL, University of Washington	RCV000148368	SCV000190060	uncertain significance	Familial adenomatous polyposis 1	2014-06-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000587871	SCV001551610	uncertain significance	not provided		no assertion criteria provided	clinical testing	The APC p.Arg1640Trp variant was identified in 1 of 224 proband chromosomes (frequency: 0.004) from individuals or families with familial adenomatous polyposis (Scott 2004). The variant was also identified in dbSNP (ID: rs373440614) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by GeneDx, Invitae, Color, Ambry Genetics and two clinical laboratories), Cosmic (1x in Stomach tissue), and in LOVD 3.0 (1x). The variant was not identified in COGR, MutDB, UMD-LSDB, or the Zhejiang University database. The variant was identified in 20 of 276908 chromosomes at a frequency of 0.00007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6458 chromosomes (freq: 0.0002), European in 18 of 126442 chromosomes (freq: 0.0001), East Asian in 1 of 18864 chromosomes (freq: 0.00005); it was not observed in the African, Latino, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Arg1640 residue is conserved across mammals and other organisms, and 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.