ClinVar Miner

Submissions for variant NM_000038.6(APC):c.295C>T (p.Arg99Trp) (rs139196838)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122769 SCV000166026 benign Familial adenomatous polyposis 1 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129141 SCV000183862 likely benign Hereditary cancer-predisposing syndrome 2018-06-25 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification;Subpopulation frequency in support of benign classification
GeneDx RCV000200967 SCV000209562 likely benign not specified 2017-11-09 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
University of Washington Department of Laboratory Medicine, University of Washington RCV000210128 SCV000266004 uncertain significance Colorectal cancer, susceptibility to 2016-03-25 criteria provided, single submitter clinical testing
Counsyl RCV000122769 SCV000488165 uncertain significance Familial adenomatous polyposis 1 2016-01-15 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000200967 SCV000538295 uncertain significance not specified 2017-01-10 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Seen in one 38 year old with no polyps. Penetrance of APC is close to 100%. MaxMAF is 0.064% (higher than frequency of FAP).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589216 SCV000600070 benign not provided 2019-04-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129141 SCV000681566 likely benign Hereditary cancer-predisposing syndrome 2016-03-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589216 SCV000694022 benign not provided 2016-04-18 criteria provided, single submitter clinical testing Variant summary: The APC c.295C>T variant affects a non-conserved nucleotide, resulting in an amino acid change from a large size and basic Arg to a large size and aromatic Trp. 5/5 in-silico tools predict a damaging outcome for this variant, but these predictions have not been verified with functional studies. This variant was found in 48/121376 control chromosomes at a frequency of 0.0003955, which is about 7 times the maximal expected frequency of a pathogenic APC allele (0.0000602), suggesting this variant is benign. Furthermore, the variant was shown not to co-segregate with disease in one family (Dobbie_Eur J Cancer_1994), and the variant was reported to co-occur with deleterious APC variants, p.S1222X and large deletion of exon 15, respectively (Kerr_JMD_2013). In addition, several clinical laboratories classified this variant as benign/likely benign. Taken together, this variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000589216 SCV000885015 uncertain significance not provided 2018-01-09 criteria provided, single submitter clinical testing The APC c.295C>T, p.Arg99Trp variant (rs139196838) has been reported in patients with attenuated familial adenomatous polyposis (Heinimann 2001, Jelsig 2016, Mindel 2011, Out 2015), but has also been found in trans with another APC pathogenic variant (Kerr 2013). The variant is listed in ClinVar (Variation ID: 135695), and observed in the general population at an overall frequency of 0.04% (115/277190 alleles) in the Genome Aggregation Database. The arginine at residue 99 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that the variant has an impact on the protein. Due to the limited information regarding this variant, its clinical significance could not be determined with certainty. References: Heinimann K et al. Nontruncating APC germ-line mutations and mismatch repair deficiency play a minor role in APC mutation-negative polyposis. Cancer Res. 2001; 61(20):7616-22. Jelsig A et al. Germline variants in Hamartomatous Polyposis Syndrome-associated genes from patients with one or few hamartomatous polyps. Scand J Gastroenterol. 2016; 51(9):1118-25. Kerr S et al. APC germline mutations in individuals being evaluated for familial adenomatous polyposis: a review of the Mayo Clinic experience with 1591 consecutive tests. J Mol Diagn. 2013; 15(1):31-43. Minde D et al. Messing up disorder: how do missense mutations in the tumor suppressor protein APC lead to cancer? Mol Cancer. 2011; 10:101. Out A et al. High-resolution melting (HRM) re-analysis of a polyposis patients cohort reveals previously undetected heterozygous and mosaic APC gene mutations. Fam Cancer. 2015; 14(2):247-57.
Mendelics RCV000122769 SCV001136869 likely benign Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000589216 SCV001154453 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000122769 SCV000190054 uncertain significance Familial adenomatous polyposis 1 2014-06-01 no assertion criteria provided research
Mayo Clinic Laboratories, Mayo Clinic RCV000200967 SCV000256960 uncertain significance not specified no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353757 SCV000591023 likely benign Carcinoma of colon no assertion criteria provided clinical testing The APC p.Arg99Trp variant was identified in 7 of 3802 proband chromosomes (frequency: 0.002) from individuals or families with hamartomatous polyposis syndrome and familial adenomatous polyposis (Dobbie 1996, Heinimann 2001, Out 2015, Jelsig 2016, Kerr 2013). The variant was identified in dbSNP (rs139196838) as “with uncertain significance, other allele”, ClinVar (classified as uncertain significance by Counsyl, Mayo Clinic, Quest Diagnostics and 4 other submitters, likely benign by Color, Ambry Genetics, GeneDx and Sinai Health System and benign by Invitae and Integrated Genetics), LOVD 3.0 (observed 11x) and UMD-LSDB. The variant was identified in control databases in 113 of 282,846 chromosomes at a frequency of 0.0004 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: European in 95 of 129,170 chromosomes (freq: 0.0007), African in 9 of 24,968 chromosomes (freq: 0.0004), Other in 2 of 7224 chromosomes (freq: 0.0003), Finnish in 3 of 25,118 chromosomes (freq: 0.0001), Latino in 3 of 35,436 chromosomes (freq: 0.00009), East Asian in 1 of 19,944 chromosomes (freq: 0.00005), while the variant was not observed in the Ashkenazi Jewish and South Asian populations. The variant was identified in individuals in trans with pathogenic APC variants (p.Ser1222* and exon 15 deletion) (Kerr 2013). The p.Arg99 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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