Submissions for variant NM_000038.6(APC):c.3173A>G (p.Asp1058Gly)

gnomAD frequency: 0.00056  dbSNP: rs148725540

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120013	SCV000148988	likely benign	not specified	2017-12-19	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.
Ambry Genetics	RCV000115079	SCV000172904	benign	Hereditary cancer-predisposing syndrome	2014-07-21	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Invitae	RCV003743549	SCV000219052	benign	Familial adenomatous polyposis 1	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000350760	SCV000452001	likely benign	APC-Associated Polyposis Disorders	2017-04-28	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Counsyl	RCV000168362	SCV000487857	uncertain significance	Familial adenomatous polyposis 1	2015-11-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115079	SCV000681584	likely benign	Hereditary cancer-predisposing syndrome	2016-03-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000034408	SCV000805389	likely benign	not provided	2017-08-28	criteria provided, single submitter	clinical testing
Mendelics	RCV003492324	SCV000838099	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120013	SCV000887516	benign	not specified	2021-09-30	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120013	SCV000916492	benign	not specified	2021-11-08	criteria provided, single submitter	clinical testing	Variant summary: APC c.3173A>G (p.Asp1058Gly) results in a non-conservative amino acid change located in the Adenomatous polyposis coli (APC) family (IPR026818) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0006 in 250576 control chromosomes, predominantly at a frequency of 0.00074 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 10 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. c.3173A>G has been reported in the literature in individuals affected with Familial Adenomatous Polyposis, colorectal cancer, as well as unaffected individuals, without strong evidence for causality (e.g. Kerr_2013, Out_2015, Ghatak_2017, Johnston_2012). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. Co-occurrences with other pathogenic variants has been reported (APC c.2016_2017delTA, p.His672GlnfsX7, UMD; unspecified variants, Kerr_2013), providing supporting evidence for a benign role. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=6), variant of uncertain significance (n=3) and benign (n=2). Based on the evidence outlined above, the variant was classified as benign.
Baylor Genetics	RCV000168362	SCV001529361	uncertain significance	Familial adenomatous polyposis 1	2018-02-16	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000168362	SCV001775519	likely benign	Familial adenomatous polyposis 1	2021-08-05	criteria provided, single submitter	clinical testing	The APC c.3173A>G (p.Asp1058Gly) missense change has a maximum non-founder subpopulation frequency of 0.072% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/5-112174464-A-G). This is higher than the reported incidence of APC-related familial adenomatous polyposis (BS1). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in non-cancer control subjects and individuals without a phenotype suggestive of APC-related familial adenomatous polyposis (PMID: 30267214, internal data). This variant has been reported to co-occur with known pathogenic variants in APC (BP2; PMID: 23159591, UMD database). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP2.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034408	SCV002048836	likely benign	not provided	2023-09-08	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115079	SCV002530773	benign	Hereditary cancer-predisposing syndrome	2020-10-18	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120013	SCV002550612	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034408	SCV004011612	likely benign	not provided	2023-06-01	criteria provided, single submitter	clinical testing	APC: BP2, BS1
Myriad Genetics, Inc.	RCV000168362	SCV004018800	benign	Familial adenomatous polyposis 1	2023-02-22	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034408	SCV000043118	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000120013	SCV000084143	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000115079	SCV000805207	likely benign	Hereditary cancer-predisposing syndrome	2018-05-09	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000034408	SCV001550252	likely benign	not provided		no assertion criteria provided	clinical testing	The APC p.Asp1058Gly variant was identified in 3 of 3262 proband chromosomes (frequency: 0.001) from individuals or families with gastric cancer or FAP (Ghatak 2017, Kerr 2013). The variant was also identified in dbSNP (ID: rs148725540) as “With other allele”, ClinVar (classified as benign by Ambry Genetics, Invitae; as likely benign by Color Genomics; as uncertain significance by Counsyl and one clinical laboratory), Clinvitae, Cosmic (2x in diffuse adenocarcinoma), MutDB, LOVD 3.0 (6x conflicting interpretations of pathogenicity), and in UMD-LSDB (6x likely neutral). In UMD the variant was identified with a co-occurring pathogenic APC variant (c.2016_2017delTA,p.His672GlnfsX7), increasing the likelihood that the p.Asp1058Gly variant does not have clinical significance. The variant was not identified in GeneInsight-COGR, or Zhejiang University databases. The variant was identified in control databases in 165 of 276366 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 9 of 24010 chromosomes (freq: 0.0004), Other in 1 of 6458 chromosomes (freq: 0.0002), Latino in 8 of 34390 chromosomes (freq: 0.0002), European in 93 of 126014 chromosomes (freq: 0.001), Finnish in 29 of 25782 chromosomes (freq: 0.001), and South Asian in 25 of 30766 chromosomes (freq: 0.001), while the variant was not observed in the Ashkenazi Jewish, or East Asian, populations. The p.Asp1058 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000034408	SCV001743597	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000034408	SCV001807236	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000034408	SCV001923642	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000034408	SCV001958472	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000034408	SCV001967071	likely benign	not provided		no assertion criteria provided	clinical testing