ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.1379T>C (p.Met460Thr) (rs758309022)

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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 RCV000164562 SCV000215220 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000482353 SCV000571662 uncertain significance not provided 2016-09-14 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.1379T>C at the cDNA level, p.Met460Thr (M460T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant was reported in an individual with a history of tubular adenoma, hyperplastic polyp, and rectal neuroendocrine tumor, however, the variant did not segregate with cancer nor polyposis in the large pedigree (Hansen 2015). BMPR1A Met460Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BMPR1A Met460Thr occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located in the Protein kinase and IC domain (Howe 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BMPR1A Met460Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000164562 SCV000682861 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763677 SCV000894557 uncertain significance Juvenile polyposis syndrome; Hereditary mixed polyposis syndrome 2 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000796815 SCV000936343 uncertain significance Juvenile polyposis syndrome 2018-08-26 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 460 of the BMPR1A protein (p.Met460Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs758309022, ExAC 0.01%). This variant has been reported in a family affected with several types of cancer. However, this family also carried rare variants in other genes (PMID: 25860647). ClinVar contains an entry for this variant (Variation ID: 185192). 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 tolerated, but 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.

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