Submissions for variant NM_004329.3(BMPR1A):c.1216C>T (p.Arg406Cys)

gnomAD frequency: 0.00004  dbSNP: rs587781332

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129084	SCV000183788	benign	Hereditary cancer-predisposing syndrome	2022-02-01	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001293444	SCV000288384	likely benign	Juvenile polyposis syndrome	2024-10-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000233959	SCV000488745	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2016-06-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000519920	SCV000618117	uncertain significance	not provided	2022-09-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with colorectal cancer or idiopathic pulmonary arterial hypertension in the published literature (Raskin et al., 2017; Zhu et al., 2019); This variant is associated with the following publications: (PMID: 29212164, 27930734, 31727138)
Color Diagnostics, LLC DBA Color Health	RCV000129084	SCV000906005	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 406 of the BMPR1A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer in the literature (PMID 29212164). This variant has been identified in 22/282846 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.
Sema4, Sema4	RCV000129084	SCV002528558	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV001293444	SCV004019494	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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001293444	SCV005689361	uncertain significance	Juvenile polyposis syndrome	2024-07-25	criteria provided, single submitter	clinical testing	The BMPR1A c.1216C>T (p.Arg406Cys) missense change has a maximum subpopulation frequency of 0.0023% in gnomAD v2.1.1. The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with colorectal cancer (PMID: 29212164). To our knowledge, this variant has not been reported in individuals with juvenile polyposis syndrome. A missense variant in the same amino acid residue, R406L, was reported in one individual presenting syndromic features (PMID: 31493347). Functional studies on chondrocytes with R406L showed increased cell death, altered BMP signaling, and reduced Sox9 expression. Western blot and immunofluorescence analyses demonstrated changes in canonical and noncanonical BMP pathways (PMID: 31493347). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.