ClinVar Miner

Submissions for variant NM_000038.6(APC):c.2586C>G (p.Asn862Lys) (rs147972247)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000590530 SCV000209502 likely benign not provided 2020-09-28 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24728327, 25980754, 27156442, 27882345)
Invitae RCV000200489 SCV000252911 benign Familial adenomatous polyposis 1 2020-12-04 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000290687 SCV000451997 benign APC-Associated Polyposis Disorders 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Ambry Genetics RCV000492033 SCV000579789 likely benign Hereditary cancer-predisposing syndrome 2018-09-14 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign);Other data supporting benign classification
Color Health, Inc RCV000492033 SCV000681536 likely benign Hereditary cancer-predisposing syndrome 2016-06-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590530 SCV000694014 benign not provided 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The APC c.2586C>G (p.Asn862Lys) variant involves the alteration of a conserved nucleotide and 2/3 in silico tools (Mutation Taster and SNPsandGo not captured here due to low p-value and reliability index value, respectively) predict a benign outcome. However, these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 55/121326 (1/2206), predominantly in the South Asian cohort, 44/16508 (1/375), which does exceed the estimated maximal expected allele frequency for a pathogenic APC variant of 1/14005/ Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of South Asian origin. Multiple publications have cited the variant in affected individuals, although with limited information (ie, lack of cosegregation data). In addition, multiple clinical diagnostic laboratories classified this variant as "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign.
Counsyl RCV000200489 SCV000786296 likely benign Familial adenomatous polyposis 1 2018-04-05 criteria provided, single submitter clinical testing
ITMI RCV000120023 SCV000084153 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356185 SCV001551280 likely benign Carcinoma of colon no assertion criteria provided clinical testing The APC p.Asn862Lys variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome and was present in 1 of 1362 control chromosomes (frequency: 0.0007) from healthy individuals (Bodian 2014, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs147972247) as "With Likely benign allele", ClinVar (classified as benign by Invitae and Integrated Genetics/Laboratory Corporation of America; as likely benign by GeneDx, Ambry Genetics and three other submitters), Cosmic (1x in large intestine tissue), and LOVD 3.0 (1x likely benign). The variant was not identified in COGR, MutDB, UMD-LSDB, or Zhejiang University databases. The variant was identified in control databases in 103 of 276786 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: South Asian in 82 of 30778 chromosomes (freq: 0.003), Other in 3 of 6458 chromosomes (freq: 0.0005), European in 16 of 126320 chromosomes (freq: 0.0001), and Latino in 2 of 34414 chromosomes (freq: 0.00006); it was not observed in the African, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Asn862 residue is not conserved in mammals and 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 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.