ClinVar Miner

Submissions for variant NM_000038.6(APC):c.3173A>G (p.Asp1058Gly) (rs148725540)

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Total submissions: 20
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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 Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign)
Invitae RCV000168362 SCV000219052 benign Familial adenomatous polyposis 1 2020-12-08 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Health, Inc RCV000115079 SCV000681584 likely benign Hereditary cancer-predisposing syndrome 2016-03-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034408 SCV000805389 likely benign not provided 2017-08-28 criteria provided, single submitter clinical testing
Mendelics RCV000168362 SCV000838099 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034408 SCV000887516 benign not provided 2017-08-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120013 SCV000916492 likely benign not specified 2019-10-04 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 (gnomAD). The observed variant frequency is approximately 8.4 fold the estimated maximal allele frequency expected for a pathogenic variant in APC causing Familial Adenomatous Polyposis phenotype (7.1e-05), strongly suggesting that the variant is benign. 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 have been reported (APC c.2016_2017delTA, p.His672GlnfsX7, UMD; unspecified variants, Kerr_2013), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submissions to ClinVar (evaluation after 2014) have cited the variant with conflicting assessments (2x benign, 5x likely benign, 2x uncertain significance). Based on the evidence outlined above, the variant was classified as likely 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 Clinical Genomics Lab, 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.
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
Human Genetics - Radboudumc,Radboudumc RCV000034408 SCV001958472 likely benign not provided no assertion criteria provided clinical testing

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