Submissions for variant NM_004329.3(BMPR1A):c.519C>G (p.Cys173Trp)

dbSNP: rs863224721

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000573423	SCV000668294	uncertain significance	Hereditary cancer-predisposing syndrome	2024-03-14	criteria provided, single submitter	clinical testing	The p.C173W variant (also known as c.519C>G), located in coding exon 5 of the BMPR1A gene, results from a C to G substitution at nucleotide position 519. The cysteine at codon 173 is replaced by tryptophan, an amino acid with highly dissimilar properties. This variant has been detected in multiple individuals with no reported features of Juvenile polyposis syndrome (JPS) (Ambry internal data). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000573423	SCV000912934	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-15	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tryptophan at codon 173 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001322804	SCV001513693	uncertain significance	Juvenile polyposis syndrome	2025-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 173 of the BMPR1A protein (p.Cys173Trp). 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: 216583). 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.
Baylor Genetics	RCV003474962	SCV004212620	uncertain significance	Polyposis syndrome, hereditary mixed, 2	2024-03-20	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001322804	SCV004842863	uncertain significance	Juvenile polyposis syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with tryptophan at codon 173 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.
PreventionGenetics, part of Exact Sciences	RCV004754353	SCV005367228	uncertain significance	BMPR1A-related disorder	2024-08-30	no assertion criteria provided	clinical testing	The BMPR1A c.519C>G variant is predicted to result in the amino acid substitution p.Cys173Trp. To our knowledge, this variant has not been reported in the literature or in gnomAD, indicating this variant is rare. This variant is classified as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/216583/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.