ClinVar Miner

Submissions for variant NM_000038.6(APC):c.1589T>C (p.Val530Ala) (rs202199891)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206690 SCV000259451 uncertain significance Familial adenomatous polyposis 1 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 530 of the APC protein (p.Val530Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs202199891, ExAC 0.005%). This variant has been reported in individuals affected with polyposis and colorectal adenomas (PMID: 22976915, 23159591, 22773231). ClinVar contains an entry for this variant (Variation ID: 219535). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000657022 SCV000292867 uncertain significance not provided 2017-11-16 criteria provided, single submitter clinical testing This variant is denoted APC c.1589T>C at the cDNA level, p.Val530Ala (V530A) at the protein level, and results in the change of a Valine to an Alanine (GTG>GCG). This variant has been observed in at least two individuals with multiple colorectal adenomas or polyposis, an individual being evaluated for Familial Adenomatous Polyposes (FAP), as well as an individual with colorectal cancer (de Leon 2013, Kerr 2013, Urso 2013, Yurgelun 2017). APC Val530Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. APC Val530Ala is located in the Armadillo region (Azzopardi 2008). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether APC Val530Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000566249 SCV000667219 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000566249 SCV000681476 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-07 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000235972 SCV000731347 uncertain significance not specified 2016-12-02 criteria provided, single submitter clinical testing The p.Val530Ala variant in APC has been reported in three individuals: 1 with a ttenuated familial adenomatous polyposis (AFAP; de Leon 2013), 1 with multiple colorectal adenomas (Urso 2013), and 1 with suspected FAP (Kerr 2013). This vari ant has also been identified in 3/66436 of European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs202199891). C omputational prediction tools and conservation analysis suggest that the p.Val53 0Ala variant may impact the protein, though this information is not predictive e nough to determine pathogenicity. In summary, the clinical significance of the p .Val530Ala variant is uncertain.
GeneKor MSA RCV000566249 SCV000821808 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000206690 SCV000838077 uncertain significance Familial adenomatous polyposis 1 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000235972 SCV000916500 uncertain significance not specified 2018-07-10 criteria provided, single submitter clinical testing Variant summary: APC c.1589T>C (p.Val530Ala) affects a conserved nucleotide and results in a non-conservative amino acid change located in an Armadillo repeat domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 245588 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1589T>C has been reported in the literature in individuals affected with Familial Adenomatous Polyposis (FAP) (Kerr 2013), attenuated FAP (AFAP) (deLeon 2013, Urso 2012) and Colorectal Cancer (Yurgelun 2017). These reports do not provide unequivocal conclusions about association of the variant with Familial Adenomatous Polyposis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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