ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.733T>A (p.Tyr245Asn) (rs369012159)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130665 SCV000185551 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000231232 SCV000288400 uncertain significance Juvenile polyposis syndrome 2018-11-18 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with asparagine at codon 245 of the BMPR1A protein (p.Tyr245Asn). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and asparagine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 141942). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Counsyl RCV000231232 SCV000488805 uncertain significance Juvenile polyposis syndrome 2016-06-20 criteria provided, single submitter clinical testing
GeneDx RCV000589200 SCV000616656 uncertain significance not provided 2019-01-07 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.733T>A at the cDNA level, p.Tyr245Asn (Y245N) at the protein level, and results in the change of a Tyrosine to an Asparagine (TAT>AAT). This variant had been reported in an individual with colorectal cancer (Yurgelun 2017). BMPR1A Tyr245Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). BMPR1A Tyr245Asn is located in the protein kinase domain (Howe 2004, Uniprot). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BMPR1A Tyr245Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130665 SCV000682914 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589200 SCV000698324 uncertain significance not provided 2016-07-01 criteria provided, single submitter clinical testing Variant summary: The BMPR1A c.733T>A (p.Tyr245Asn) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. Tyr245 is located in the protein kinase domain of Bone morphogenetic protein receptor type-1A. This variant was found in 1/120952 control chromosomes at a frequency of 0.0000083, which is approximately 4 times the estimated maximal expected allele frequency of a pathogenic BMPR1A variant (0.000002), suggesting this variant could be a benign polymorphism. However, it cannot be ruled out that this individual was affected, since the ExAC database is a general population database, not a healthy control database. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. In addition, one clinical diagnostic laboratory classified this variant as a VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589200 SCV000887609 uncertain significance not provided 2017-09-14 criteria provided, single submitter clinical testing

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