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

gnomAD frequency: 0.00009  dbSNP: rs147972247

Total submissions: 18

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)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200489	SCV000252911	benign	Familial adenomatous polyposis 1	2024-01-30	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	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
Sema4, Sema4	RCV000492033	SCV002537733	benign	Hereditary cancer-predisposing syndrome	2020-11-03	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120023	SCV002550602	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590530	SCV002586068	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	APC: BS1
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000200489	SCV004017616	benign	Familial adenomatous polyposis 1	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000200489	SCV004018767	likely benign	Familial adenomatous polyposis 1	2023-02-21	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590530	SCV004222290	benign	not provided	2022-09-08	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997329	SCV004839700	likely benign	Classic or attenuated familial adenomatous polyposis	2024-02-05	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.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590530	SCV002037390	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000590530	SCV002037983	likely benign	not provided		no assertion criteria provided	clinical testing