ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.1333A>G (p.Ile445Val) (rs587781503)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129478 SCV000184248 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000484454 SCV000566353 uncertain significance not provided 2018-10-04 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.1333A>G at the cDNA level, p.Ile445Val (I445V) at the protein level, and results in the change of an Isoleucine to a Valine (ATC>GTC). This variant has been observed in at least one individual with colorectal cancer (Yurgelun 2017). BMPR1A Ile445Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the protein kinase domain (UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BMPR1A Ile445Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000557878 SCV000632694 uncertain significance Juvenile polyposis syndrome 2018-09-28 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 445 of the BMPR1A protein (p.Ile445Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs587781503, ExAC 0.03%). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 141113). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Color RCV000129478 SCV000903823 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779844 SCV000916695 uncertain significance not specified 2018-07-02 criteria provided, single submitter clinical testing Variant summary: BMPR1A c.1333A>G (p.Ile445Val) results in a conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function (MutationTaster not captured here due to low p-value). The variant allele was found at a frequency of 2.4e-05 in 246270 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1333A>G, has been reported in the literature in an individual affected with colorectal cancer (Yurgelun_2017). This report does not provide an unequivocal conclusion about association of the variant with Juvenile Polyposis Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submission from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.

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