Submissions for variant NM_004329.3(BMPR1A):c.749T>C (p.Met250Thr)

gnomAD frequency: 0.00001  dbSNP: rs587780783

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000123229	SCV000166535	likely benign	Juvenile polyposis syndrome	2023-12-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000164314	SCV000214945	benign	Hereditary cancer-predisposing syndrome	2023-04-26	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	RCV000586264	SCV000567755	likely benign	not provided	2023-04-10	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235047	SCV000698325	likely benign	not specified	2023-05-05	criteria provided, single submitter	clinical testing	Variant summary: BMPR1A c.749T>C (p.Met250Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251380 control chromosomes, predominantly at a frequency of 0.00026 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuas in the gnomAD database is approximately 130 fold of the estimated maximal expected allele frequency for a pathogenic variant in BMPR1A, suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. c.749T>C has been reported in the literature in an individual with Lynch Syndrome (Yurlegun_2015). This report does not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25980754). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified as Likely Benign (n=2) and VUS (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000164314	SCV001352930	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-13	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 250 of the BMPR1A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 9/251380 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	RCV000586264	SCV004222537	uncertain significance	not provided	2022-11-11	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00026 (9/34576 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in an individual with a Lynch syndrome associated cancer and/or polyps (PMID: 25980754 (2015)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000123229	SCV004842891	uncertain significance	Juvenile polyposis syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 250 of the BMPR1A protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on protein structure and function. This variant has been reported in an individual affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 25980754). This variant has been identified in 9/251380 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.