Submissions for variant NM_004329.3(BMPR1A):c.1243G>A (p.Glu415Lys)

gnomAD frequency: 0.00051  dbSNP: rs140592056

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000034700	SCV000149735	likely benign	not provided	2020-11-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 27621404, 25722345, 27878467, 24728327, 25637381, 25980754, 22703879, 23399955, 25801821, 27153395, 27884173, 24448499, 30680046)
Invitae	RCV001507226	SCV000153921	benign	Juvenile polyposis syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115826	SCV000187390	likely benign	Hereditary cancer-predisposing syndrome	2018-10-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Illumina Laboratory Services, Illumina	RCV000119185	SCV000365652	likely benign	Generalized juvenile polyposis/juvenile polyposis coli	2018-06-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000115826	SCV000537412	likely benign	Hereditary cancer-predisposing syndrome	2016-05-19	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000120252	SCV000538421	uncertain significance	not specified	2016-10-31	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is present in HGMD in 5 papers, with comments suggesting likely benign. The variant is present in ExAC at a Max MAF of 0.11% and at 1.6% (165) of Ashkenazi alleles in gnomAD - frequency too high for disease. It is classified as Likely Benign by 4 submitters (GeneDx, Invitae, Ambry, CSER_CC_NCGL) and as VUS by Biesecker lab.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000034700	SCV000698308	benign	not provided	2016-09-02	criteria provided, single submitter	clinical testing	Variant summary: The BMPR1A c.1243G>A (p.Glu415Lys) variant involves the alteration of a conserved nucleotide. Glu415Lys occurs at a position that is conserved across mammals and is located in the protein kinase domain, and 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in 87/122544 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0011238 (75/66740). This frequency is about 562 times the estimated maximal expected allele frequency of a pathogenic BMPR1A variant (0.000002), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant was also observed in three individuals with a history of moderate-load polyposis; reported pathology included hyperplastic, hamartomatous, juvenile and adenomatous polyps (Ngeow 2013); and in one individual undergoing hereditary panel testing for a personal and/or family history suspicious for Lynch syndrome (Yurgelun 2015). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance or likely benign. Taken together and based on the prevalence in the general population, this variant is classified as benign.
Counsyl	RCV000119185	SCV000786169	likely benign	Generalized juvenile polyposis/juvenile polyposis coli	2018-03-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000034700	SCV000806596	likely benign	not provided	2017-12-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000119185	SCV001138111	benign	Generalized juvenile polyposis/juvenile polyposis coli	2019-05-28	criteria provided, single submitter	clinical testing
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000034700	SCV001251955	benign	not provided	2020-05-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120252	SCV002070345	likely benign	not specified	2020-01-13	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115826	SCV002528560	benign	Hereditary cancer-predisposing syndrome	2020-07-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120252	SCV002549932	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000034700	SCV002821524	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	BMPR1A: PP3, BS1
Myriad Genetics, Inc.	RCV001507226	SCV004019448	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034700	SCV004564176	likely benign	not provided	2023-09-14	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034700	SCV000043147	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.
ITMI	RCV000120252	SCV000084402	not provided	not specified	2013-09-19	no assertion provided	reference population
CSER _CC_NCGL, University of Washington	RCV000148376	SCV000190073	likely benign	Gastrointestinal polyposis	2014-06-01	no assertion criteria provided	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000034700	SCV000778627	likely benign	not provided	2018-01-24	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000115826	SCV000787887	likely benign	Hereditary cancer-predisposing syndrome	2017-09-13	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354222	SCV001548782	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	BMPR1A, EXON11, c.1243G>A, p.Glu415Lys, Heterozygous, Uncertain SignificancernThe BMPR1A p.Glu415Lys variant was identified in 15 of 11178 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer, Lynch Syndrome, or undefined moderate load gastrointestinal polyposis and was present in 2 of 1362 control chromosomes (frequency: 0.002) from healthy individuals (Balmana 2016, Ngeow 2013, Tung 2015, Yurgelun 2015, Bodian 2014). The variant was also identified in dbSNP (ID: rs140592056) as "With other allele", ClinVar (classified as benign by Invitae and Integrated Genetics/Laboratory Corporation of America; as likely benign by GeneDx, Ambry Genetics, PreventionGenetics, and six other submitters; and as uncertain significance by two submitters), and LOVD 3.0 (1x as VUS). The variant was identified in control databases in 221 of 277220 chromosomes (1 homozygous) at a frequency of 0.0008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 161 of 10152 chromosomes (freq: 0.02, increasing the likelihood this could be a low frequency benign variant), African in 1 of 24028 chromosomes (freq: 0.00004), Other in 7 of 6466 chromosomes (freq: 0.001), Latino in 10 of 34420 chromosomes (freq: 0.0003), European in 39 of 126714 chromosomes (freq: 0.0003), East Asian in 1 of 18870 chromosomes (freq: 0.00005), and South Asian in 2 of 30782 chromosomes (freq: 0.00006); it was not observed in the Finnish population. The p.Glu415 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 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.rnAssessment Date: 2019/07/23rnReferences (PMIDs): 27621404, 23399955, 25186627, 25980754, 24728327