ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5009C>T (p.Ala1670Val)

gnomAD frequency: 0.00018  dbSNP: rs202228932
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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002228429 SCV000166040 likely benign Familial adenomatous polyposis 1 2021-12-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV000128987 SCV000172877 likely benign Hereditary cancer-predisposing syndrome 2018-12-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000586353 SCV000292460 likely benign not provided 2020-11-20 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 25991819, 26336887, 26207792, 28502729, 27705013, 28944238, 30680046)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000236885 SCV000694066 likely benign not specified 2019-02-22 criteria provided, single submitter clinical testing Variant summary: APC c.5009C>T (p.Ala1670Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 281640 control chromosomes, predominantly at a frequency of 0.00033 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 4.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. This variant has been reported in individuals affected with-, or a clinical history suggestive of, adenomatous polyposis or early-onset colorectal cancer (Marabelli 2016, DeRycke 2017, Rey 2017, Henn 2019), and also found in individuals affected with- or undergoing testing for other tumor phenotypes (Lincoln 2015, Zhang 2015); however without strong evidence for causality (i.e. no co-segregation data were provided). These reports thus 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 other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000122783 SCV000784749 uncertain significance Familial adenomatous polyposis 1 2017-11-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000586353 SCV000805418 uncertain significance not provided 2017-11-20 criteria provided, single submitter clinical testing
Mendelics RCV000122783 SCV000838125 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000128987 SCV000910625 likely benign Hereditary cancer-predisposing syndrome 2016-06-24 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586353 SCV001133340 likely benign not provided 2020-03-18 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000586353 SCV001154470 uncertain significance not provided 2019-01-01 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000236885 SCV002070240 uncertain significance not specified 2021-11-19 criteria provided, single submitter clinical testing DNA sequence analysis of the APC gene demonstrated a sequence change, c.5009C>T, in exon 16 that results in an amino acid change, p.Ala1670Val. This sequence change has been described in the gnomAD database with a frequency of 0.033% in the non-Finnish European subpopulation (dbSNP rs202228932). The p.Ala1670Val change affects a highly conserved amino acid residue located in a domain of the APC protein that is not known to be functional. The p.Ala1670Val substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been previously described in an individual with multiple adenomas (PMID: 27705013). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Ala1670Val change remains unknown at this time.
Sema4,Sema4 RCV000128987 SCV002534954 likely benign Hereditary cancer-predisposing syndrome 2021-08-10 criteria provided, single submitter curation
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353632 SCV000591183 likely benign Carcinoma of colon no assertion criteria provided clinical testing The APC p.Ala1670Val variant was not identified in the literature nor was it identified in the Genesight-COGR, Cosmic, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs202228932) “With Uncertain significance allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: likely benign by Ambry Genetics and uncertain significance by Invitae, GeneDx and Department of Pathology and Laboratory Medicine (Sinai Health System)), Clinvitae (3x), Insight Colon Cancer Gene Variant Database (1X), and in control databases in 48 of 275942 chromosomes at a frequency of 0.0002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: European Non-Finnish in 41 of 125686 chromosomes (frequency: 0.0003) and European Finnish in 7 of 25768 chromosomes (frequency: 0.0003). The variant was also identified by our laboratory in 1 individual with tubular adenomas. The p.Ala1670 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of the Val variant impacting the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Mayo Clinic Laboratories,Mayo Clinic RCV000236885 SCV000691756 uncertain significance not specified no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000236885 SCV002550628 uncertain significance not specified 2022-04-12 no assertion criteria provided clinical testing

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