Submissions for variant NM_004329.3(BMPR1A):c.5C>T (p.Pro2Leu)

gnomAD frequency: 0.00001  dbSNP: rs143248687

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588955	SCV000209867	uncertain significance	not provided	2023-08-20	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Tung et al., 2015); This variant is associated with the following publications: (PMID: 27930734, 25186627, 30267214)
Counsyl	RCV000411290	SCV000488271	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2016-02-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001328518	SCV000552854	uncertain significance	Juvenile polyposis syndrome	2024-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2 of the BMPR1A protein (p.Pro2Leu). This variant is present in population databases (rs143248687, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 182062). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt BMPR1A function with a negative predictive value of 95%. 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	benign	Hereditary cancer-predisposing syndrome	2023-01-03	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000562590	SCV000682903	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 2 of the BMPR1A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627) and in an individual unaffected with cancer (PMID: 27930734). This variant has been identified in 7/282724 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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
Myriad Genetics, Inc.	RCV001328518	SCV004019453	uncertain significance	Juvenile polyposis syndrome	2023-03-02	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV001328518	SCV004840676	uncertain significance	Juvenile polyposis syndrome	2024-06-11	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 2 of the BMPR1A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627) and in an individual unaffected with cancer (PMID: 27930734). This variant has been identified in 7/282724 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.