ClinVar Miner

Submissions for variant NM_000038.6(APC):c.607C>G (p.Gln203Glu) (rs141576417)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120051 SCV000149018 benign not specified 2018-01-31 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.
Invitae RCV000987552 SCV000166046 benign Familial adenomatous polyposis 1 2020-12-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115109 SCV000186254 benign Hereditary cancer-predisposing syndrome 2015-08-19 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Other data supporting benign classification;Other strong data supporting benign classification
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000120051 SCV000538294 likely benign not specified 2016-12-14 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: This variant is present in 1.2% of Ashkenazi Jewish alleles in gnomAD (121/10150). Frequency too high for disease. It is classified in ClinVar with 1 star as Likely benign/benign by Invitae and Ambry and as VUS by GeneDx and Biesecker lab.
Color Health, Inc RCV000115109 SCV000681776 likely benign Hereditary cancer-predisposing syndrome 2016-09-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120051 SCV000694089 likely benign not specified 2020-08-13 criteria provided, single submitter clinical testing Variant summary: APC c.607C>G (p.Gln203Glu) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 251556 control chromosomes (gnomAD). The observed variant frequency is approximately 9 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 benign. c.607C>G has been reported in the literature in individuals affected with adrenocortical carcinoma and ependymoma (Zhang_2015), endometrial cancer (Kogan_2018), and male breast cancer (Rizzolo_2019). These reports however, do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Co-occurrence with another pathogenic variant has been reported (BRCA1 c.68_69delAG, p.Glu23ValfsX17) in our internal database, providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 other ClinVar submitters (evaluation after 2014) cite the variant as likely benign/benign (n=10) or uncertain significance (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000034394 SCV000805445 likely benign not provided 2017-09-15 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine, University of Washington RCV000757929 SCV000886450 likely benign Familial multiple polyposis syndrome 2018-05-29 criteria provided, single submitter research The APC variant designated as NM_000038.5:c.607C>G (p.Gln203Glu) is classified as likely benign. This variant is found in approximately 1 out of 500 individuals of European ancestry (, which is a higher frequency than expected of a pathogenic APC variant (Kobayashi et al, 2017, PMID:28166811). It is listed in the ClinVar database (Variation ID: 41509) and has been classified as benign or likely benign by 7 clinical laboratories. In one obseved family, this variant was identified in two members who have been documented to have fewer than 5 colon polyps on colonoscopy. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter APC function or modify cancer risk. A modest (less than 2-fold) increase in risk of cancer or colon polyps due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034394 SCV000888754 benign not provided 2018-05-08 criteria provided, single submitter clinical testing
Mendelics RCV000987552 SCV001136875 likely benign Familial adenomatous polyposis 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001156934 SCV001318474 uncertain significance APC-Associated Polyposis Disorders 2019-05-29 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034394 SCV000043106 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
ITMI RCV000120051 SCV000084187 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000115109 SCV000693485 likely benign Hereditary cancer-predisposing syndrome 2017-09-28 no assertion criteria provided clinical testing
GenomeConnect, ClinGen RCV000709878 SCV000840215 not provided Desmoid disease, hereditary; Familial adenomatous polyposis 1 no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000987552 SCV001551222 likely benign Familial adenomatous polyposis 1 no assertion criteria provided clinical testing The APC p.Gln203Glu variant was identified in the literature in 5 of 2506 control chromosomes (frequency: 0.002) from individuals with no personal or family history of cancer (Johnston 2012, Bodian 2014). The variant was also identified in dbSNP (ID: rs141576417) as "With other allele", ClinVar (classified as benign by Invitae, Ambry Genetics and GeneDx; as likely benign by Prevention Genetics, Color, and three other submitters; and as uncertain significance by one submitter), UMD (4x as "unclassified variant"), and LOVD 3.0 (1x). The variant was identified in control databases in 155 of 276178 chromosomes at a frequency of 0.0006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 129 of 10142 chromosomes (freq: 0.01), Other in 5 of 6448 chromosomes (freq: 0.0008), European in 18 of 126044 chromosomes (freq: 0.0001), and African in 3 of 24000 chromosomes (freq: 0.0001); it was not observed in the East Asian, Finnish, Latino, or South Asian populations. The p.Gln203 residue is conserved across mammals and other organisms and 4 of 5 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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