Submissions for variant NM_004329.3(BMPR1A):c.496G>A (p.Ala166Thr)

dbSNP: rs971636078

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635426	SCV000756839	uncertain significance	Juvenile polyposis syndrome	2024-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 166 of the BMPR1A protein (p.Ala166Thr). 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: 529905). 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.
Color Diagnostics, LLC DBA Color Health	RCV000772204	SCV000905321	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 166 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 hereditary cancer 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.
Ambry Genetics	RCV000772204	SCV001185206	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	clinical testing	The p.A166T variant (also known as c.496G>A), located in coding exon 5 of the BMPR1A gene, results from a G to A substitution at nucleotide position 496. The alanine at codon 166 is replaced by threonine, an amino acid with 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.
Sema4, Sema4	RCV000772204	SCV002528604	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-22	criteria provided, single submitter	curation
GeneDx	RCV001356096	SCV002819066	uncertain significance	not provided	2022-07-07	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; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003471992	SCV004210975	uncertain significance	Polyposis syndrome, hereditary mixed, 2	2024-03-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000635426	SCV005423977	uncertain significance	Juvenile polyposis syndrome	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 166 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 hereditary cancer 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356096	SCV001551165	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BMPR1A p.Ala166Thr variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs971636078) and ClinVar (classified as Uncertain Significance for Juvenille polyposis syndrome by Invitae in 2018, and Uncertain significance associated with hereditary cancery predisposing syndrome by Color in 2018). The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Ala166 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.