ClinVar Miner

Submissions for variant NM_000038.6(APC):c.5026A>G (p.Arg1676Gly) (rs370560998)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587987 SCV000149009 likely benign not provided 2020-11-25 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 21859464, 18199528, 24055113, 24728327, 25637381, 25142776, 25980754, 26976419, 27050224, 28805986, 27882345, 28873162)
CSER _CC_NCGL, University of Washington RCV000210376 SCV000190061 uncertain significance Familial multiple polyposis syndrome 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant belongs in a lower pathogenicity class
Ambry Genetics RCV000115100 SCV000213855 likely benign Hereditary cancer-predisposing syndrome 2018-06-26 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV000148369 SCV000254020 benign Familial adenomatous polyposis 1 2020-11-27 criteria provided, single submitter clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia RCV000120016 SCV000257786 uncertain significance not specified 2015-06-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120016 SCV000694067 likely benign not specified 2021-03-01 criteria provided, single submitter clinical testing Variant summary: APC c.5026A>G (p.Arg1676Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 253514 control chromosomes (gnomAD). The observed variant frequency 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), strongly suggesting that the variant is benign. c.5026A>G has been reported in the literature in individuals affected with Familial Adenomatous Polyposis, colorectal cancer, breast cancer and ALL (Azzopardi_2008, Kraus_2015, Yurgelun_2015, Zhang_2015, Tung_2016, Alanazi_2020) but it was also detected in controls (e.g. Azzopardi_2008, Bodian_2014). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and five ClinVar submitters (evaluation after 2014) cite it as benign/likely benign. One of the submitters cites evidence of co-occurence with a mutation in another gene that clearly explains a proband's phenotype (SCV000213855.6). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000587987 SCV000805419 uncertain significance not provided 2017-06-01 criteria provided, single submitter clinical testing
Mendelics RCV000148369 SCV000838128 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000735965 SCV000864154 uncertain significance Colorectal cancer 2016-06-01 criteria provided, single submitter research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 51 year old male diagnosed with colon cancer at age 50. Family history of colorectal cancer and/or polyps. Patient also has the APC c.7399C>A variant. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Color Health, Inc RCV000115100 SCV000902642 likely benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
ITMI RCV000120016 SCV000084146 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353642 SCV000591185 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The APC p.Arg1676Gly variant was identified at a frequency of 0.003 in 2 of 660 proband chromosomes from individuals or families with FAP/MAP and colorectal cancer, and was present at a frequency of 0.001 in 1 of 1938 control chromosomes from healthy individuals matched for age, sex and race (Azzopardi 2008, Kraus 2014). In both cases the variant was identified with another variant of uncertain significance, APC p.Pro2467Thr. The variant was also identified in dbSNP (ID: rs370560998) as “With Uncertain significance allele”; NHLBI GO Exome Sequencing Project in 2 of 8600 European American chromosomes; in the Exome Aggregation Consortium database (March 14, 2016) in 16 of 120974 chromosomes (freq. 0.0001323) in the following populations: European (Non-Finnish) in 11 of 66570 chromosomes (freq. 0.0001652), South Asian in 3 of 16492 chromosomes (freq. 0.0001819), Latino in 2 of 11510 chromosomes (freq. 0.0001738), but was not seen in African, East Asian, Finnish and Other populations; Clinvitae database (4x uncertain significance); ClinVar database (uncertain significance by University of Washington Medical School, Ambry Genetics, Invitae, Division of Genomic Diagnostics-the Children’s Hospital Of Philadelphia, and GeneDx, ITMI did not provide a classification); the COGR database (uncertain significance), and UMD (1x with unclassified variant, the variant co-occurred with a non-synonymous variant c.7399C>A, p.Pro2467Thr). The p.Arg1676 residue is not conserved in mammals and the variant amino acid Glycine (Gly) is present in Platypus and Chicken, increasing the likelihood that this variant does not have clinical significance, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, 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. However, in a study looking at rare nonsynonomous variants the authors note that multiple rare inherited non-synonymous variants of APC were significantly over represented in patients who did not carry conventional pathogenic mutations in the APC or MUTYH genes. The authors felt that patients with 2 rare non-synonymous heterozygous variants, involved in ß-catenin down-regulation domain of APC protein, are likely to predispose to colorectal adenomas as compared to non FAP/MAP patients. The non-synonymous variants, c.5026A>G, R1676G and c.7399C>A, P2467T were seen together in 1 patient in their cohort and thought to together act as low penetrance disease alleles (Azzopardi 2008). 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.
True Health Diagnostics RCV000115100 SCV000787837 likely benign Hereditary cancer-predisposing syndrome 2017-12-01 no assertion criteria provided clinical testing

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