Submissions for variant NM_004329.3(BMPR1A):c.1175A>G (p.Asn392Ser)

dbSNP: rs1554891311

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522509	SCV000618319	uncertain significance	not provided	2017-03-07	criteria provided, single submitter	clinical testing	This variant is denoted BMPR1A c.1175A>G at the cDNA level, p.Asn392Ser (N392S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in small cell lung cancer (Rudin 2012). BMPR1A Asn392Ser was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. BMPR1A Asn392Ser occurs at a position where amino acids with properties similar to Asparagine are tolerated across species and is located within the protein kinase domain (Howe 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BMPR1A Asn392Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000583018	SCV000688230	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000583018	SCV002528555	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-13	criteria provided, single submitter	curation
Ambry Genetics	RCV000583018	SCV002629194	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-12	criteria provided, single submitter	clinical testing	The p.N392S variant (also known as c.1175A>G), located in coding exon 9 of the BMPR1A gene, results from an A to G substitution at nucleotide position 1175. The asparagine at codon 392 is replaced by serine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002525139	SCV002974276	uncertain significance	Juvenile polyposis syndrome	2024-05-21	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 392 of the BMPR1A protein (p.Asn392Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BMPR1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 449870). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BMPR1A protein function with a negative predictive value of 80%. 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.
All of Us Research Program, National Institutes of Health	RCV002525139	SCV005424218	uncertain significance	Juvenile polyposis syndrome	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 392 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 not been reported in individuals affected with BMPR1A-related disorders in the literature. This variant has not been identified 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.