Submissions for variant NM_004329.3(BMPR1A):c.1568A>G (p.Lys523Arg)

dbSNP: rs878854665

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000232462	SCV000288389	uncertain significance	Juvenile polyposis syndrome	2025-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 523 of the BMPR1A protein (p.Lys523Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 30093976). ClinVar contains an entry for this variant (Variation ID: 239858). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Sema4, Sema4	RCV002256165	SCV002528583	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	curation
GeneDx	RCV003332154	SCV004040280	uncertain significance	not provided	2023-03-28	criteria provided, single submitter	clinical testing	Not observed at 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 ovarian cancer (Chan et al., 2018); This variant is associated with the following publications: (PMID: 30093976)
Baylor Genetics	RCV003475080	SCV004210974	uncertain significance	Polyposis syndrome, hereditary mixed, 2	2023-09-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000232462	SCV004838523	uncertain significance	Juvenile polyposis syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 523 of the BMPR1A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/251436 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.
Ambry Genetics	RCV002256165	SCV005022053	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-09	criteria provided, single submitter	clinical testing	The p.K523R variant (also known as c.1568A>G), located in coding exon 11 of the BMPR1A gene, results from an A to G substitution at nucleotide position 1568. The lysine at codon 523 is replaced by arginine, an amino acid with highly similar properties. This alteration has been reported as a variant of unknown significance in an individual with a personal history of ovarian cancer from a cohort of 1191 cancer index patients who underwent clinical evaluation and testing with multigene panels (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.