Submissions for variant NM_004329.3(BMPR1A):c.1433G>A (p.Arg478His)

gnomAD frequency: 0.00025  dbSNP: rs113849804

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131658	SCV000186685	benign	Hereditary cancer-predisposing syndrome	2021-05-25	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Invitae	RCV002228114	SCV000260786	likely benign	Juvenile polyposis syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000034701	SCV000292499	uncertain significance	not provided	2022-09-21	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed individuals with breast cancer, colorectal cancer, or other Lynch syndrome-associated tumor (Tung et al., 2015; Yurgelun et al., 2015; DeRycke et al., 2017; Pearlman et al., 2017; Yurgelun et al., 2017; MacFarland et al., 2021); This variant is associated with the following publications: (PMID: 22703879, 28135145, 30374176, 33097490, 25186627, 25980754, 28944238, 27978560, 32522605, 33032550, 25996639, 28873162, 25801821, 30814609)
Color Diagnostics, LLC DBA Color Health	RCV000131658	SCV000537586	likely benign	Hereditary cancer-predisposing syndrome	2020-05-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034701	SCV000600220	likely benign	not provided	2019-12-24	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000515344	SCV000611440	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli; Polyposis syndrome, hereditary mixed, 2	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000235579	SCV000698313	likely benign	not specified	2021-05-09	criteria provided, single submitter	clinical testing	Variant summary: BMPR1A c.1433G>A (p.Arg478His) results in a non-conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00017 in 251494 control chromosomes, predominantly at a frequency of 0.00029 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 145 fold of the estimated maximal expected allele frequency for a pathogenic variant in BMPR1A causing Juvenile Polyposis Syndrome phenotype (2e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although c.1433G>A has been reported in the literature within settings of multigene panel testing for hereditary cancers, these report(s) do not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome (example Yurgelun_2015, Dalessandro_2015, Johnston_2012, Pearlman_2016, Tung_2014, Yurgelun_2017, Tsai_2019). A recent study reporting outcomes of re-classification of VUS from patient-driven family studies reported this variant with no cases of polyposis in a family (Tsai_2019). Co-occurrences with other pathogenic variant(s) have been reported in the literature and at our laboratory (examples, Yurgelun_2015, EPCAM deletion of exons 1-9; Our laboratory, BRCA2 c.1813dupA, p.I1605fs*11; Tsai_2019, an unspecified co-occurrence with a pathogenic variant in the PALB2 gene), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=4; VUS, n=6). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000235579	SCV000712858	uncertain significance	not specified	2016-12-28	criteria provided, single submitter	clinical testing	The p.Arg478His variant in BMPR1A has been reported in 1 individual with suspect ed Lynch Syndrome (Yurgelun 2015), 2 individuals who underwent exome sequencing for non-cancer related indications (Johnston 2012, D'Alessandro 2016) and has al so been reported in ClinVar (Variation ID 41780). This variant has also been ide ntified in 15/66738 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs113849804). Computational predict ion tools and conservation analysis suggest that the p.Arg478His variant may not impact the protein, though this information is not predictive enough to rule ou t pathogenicity. In summary, the clinical significance of the p.Arg478His varian t is uncertain.
Counsyl	RCV000203748	SCV000786297	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2018-04-05	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000203748	SCV000886442	likely benign	Generalized juvenile polyposis/juvenile polyposis coli	2018-04-30	criteria provided, single submitter	research	The BMPR1A variant designated as NM_004329.2:c.1433G>A (p.Arg478His) is classified as likely benign. This variant is listed in population databases and is found in approximately 1 out of 1750 individuals of European ancestry. In silico programs predict that this variant is likely to be tolerated (SIFT, Polyphen-2, Align-GVGD). In one observed family, this variant was not shown to segregate with colon polyps in family members who were over 60 years old. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives approimately 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter BMPR1A function or modify cancer risk. A modest (less than 2 fold) increase in cancer risk due to this variant cannot be entirely excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
CeGaT Center for Human Genetics Tuebingen	RCV000034701	SCV001148031	uncertain significance	not provided	2019-03-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131658	SCV002528572	likely benign	Hereditary cancer-predisposing syndrome	2020-10-25	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV002228114	SCV004019450	likely benign	Juvenile polyposis syndrome	2023-03-02	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034701	SCV000043148	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
GenomeConnect, ClinGen	RCV000034701	SCV001423214	not provided	not provided		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 06-21-2018 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.