Submissions for variant NM_004329.3(BMPR1A):c.1066C>T (p.Pro356Ser)

gnomAD frequency: 0.00001  dbSNP: rs774555805

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572363	SCV000668311	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-07	criteria provided, single submitter	clinical testing	The p.P356S variant (also known as c.1066C>T), located in coding exon 8 of the BMPR1A gene, results from a C to T substitution at nucleotide position 1066. The proline at codon 356 is replaced by serine, an amino acid with similar properties. This alteration was identified in one individual in a cohort of 1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps (Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001206643	SCV001377962	uncertain significance	Juvenile polyposis syndrome	2024-10-10	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 356 of the BMPR1A protein (p.Pro356Ser). This variant is present in population databases (rs774555805, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 482847). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BMPR1A protein function. 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	RCV000572363	SCV004360075	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-05	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 356 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 2/282092 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.
All of Us Research Program, National Institutes of Health	RCV001206643	SCV005424190	uncertain significance	Juvenile polyposis syndrome	2024-05-14	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 356 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). This variant has been identified in 2/282092 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV005000276	SCV005624118	uncertain significance	not provided	2024-09-02	criteria provided, single submitter	clinical testing	The BMPR1A c.1066C>T (p.Pro356Ser) variant has been reported in the published literature in individuals with Lynch syndrome-associated cancer and/or polyp (PMIDs: 25980754 (2015) and 35928693 (2022)). The frequency of this variant in the general population, 0.0000071 (2/282092 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.