Submissions for variant NM_004329.3(BMPR1A):c.1379T>C (p.Met460Thr)

gnomAD frequency: 0.00001  dbSNP: rs758309022

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164562	SCV000215220	benign	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000482353	SCV000571662	uncertain significance	not provided	2016-09-14	criteria provided, single submitter	clinical testing	This variant is denoted BMPR1A c.1379T>C at the cDNA level, p.Met460Thr (M460T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant was reported in an individual with a history of tubular adenoma, hyperplastic polyp, and rectal neuroendocrine tumor, however, the variant did not segregate with cancer nor polyposis in the large pedigree (Hansen 2015). BMPR1A Met460Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BMPR1A Met460Thr occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located in the Protein kinase and IC domain (Howe 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BMPR1A Met460Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000164562	SCV000682861	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 460 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 been reported in an individuals affected with a tubular adenoma, a hyperplastic polyp and a rectal neuroendocrine tumour (PMID: 25860647). This variant has been identified in 8/251492 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.
Fulgent Genetics, Fulgent Genetics	RCV000763677	SCV000894557	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli; Polyposis syndrome, hereditary mixed, 2	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000796815	SCV000936343	uncertain significance	Juvenile polyposis syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 460 of the BMPR1A protein (p.Met460Thr). This variant is present in population databases (rs758309022, gnomAD 0.007%). This missense change has been observed in individual(s) with BMPR1A-related conditions (PMID: 25860647). ClinVar contains an entry for this variant (Variation ID: 185192). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) 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.
All of Us Research Program, National Institutes of Health	RCV000796815	SCV004836009	uncertain significance	Juvenile polyposis syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 460 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 been reported in an individuals affected with a tubular adenoma, a hyperplastic polyp and a rectal neuroendocrine tumour (PMID: 25860647). This variant has been identified in 8/251492 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.