ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.5C>T (p.Pro2Leu) (rs143248687)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588955 SCV000209867 uncertain significance not provided 2017-09-25 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.5C>T at the cDNA level, p.Pro2Leu (P2L) at the protein level, and results in the change of a Proline to a Leucine (CCT>CTT). This variant has been identified in a deceased individual through whole genome sequencing, however, health history was not provided (He 2016). BMPR1A Pro2Leu was not observed at a significant frequency in large population cohorts (Lek 2016). Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. BMPR1A Pro2Leu occurs at a position that is not conserved and is located within the signal peptide (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 Pro2Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000411290 SCV000488271 uncertain significance Juvenile polyposis syndrome 2016-02-10 criteria provided, single submitter clinical testing
Invitae RCV000411290 SCV000552854 uncertain significance Juvenile polyposis syndrome 2018-12-08 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 2 of the BMPR1A protein (p.Pro2Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is present in population databases (rs143248687, ExAC 0.01%). This variant has been reported in an individual with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 182062). 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.
Ambry Genetics RCV000562590 SCV000668306 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000562590 SCV000682903 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588955 SCV000698318 uncertain significance not provided 2017-02-09 criteria provided, single submitter clinical testing Variant summary: The c.5C>T (p.Pro2Leu) in BMPR1A gene is a missense change that involves a non-conserved nucleotide and 2/5 in silico tools predict benign outcome. The variant of interest is located outside of any known functional domain. The variant is present in the control population dataset of ExAC at a frequency of 1.648e-05 (2/121358 chrs tested). The variant has been cited in a cohort in the literature without phenotype data provided and was cited as a VUS by reputable databases/clinical laboratories. Taking together, the variant was classified as VUS.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588955 SCV000887605 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing

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