ClinVar Miner

Submissions for variant NM_004329.3(BMPR1A):c.1243G>A (p.Glu415Lys) (rs140592056)

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Total submissions: 17
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120252 SCV000149735 likely benign not specified 2017-12-19 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV001507226 SCV000153921 benign Juvenile polyposis syndrome 2020-12-08 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 Other data supporting benign classification;Subpopulation frequency in support of benign classification
Illumina Clinical Services Laboratory,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 Health, Inc RCV000115826 SCV000537412 likely benign Hereditary cancer-predisposing syndrome 2016-05-19 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare 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,PreventionGenetics 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
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

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