ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.953A>G (p.Tyr318Cys) (rs587778111)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567105 SCV000675951 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000567105 SCV000682924 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-15 criteria provided, single submitter clinical testing
Counsyl RCV000410175 SCV000489687 uncertain significance Juvenile polyposis syndrome 2016-11-08 criteria provided, single submitter clinical testing
GeneDx RCV000656785 SCV000149739 uncertain significance not provided 2017-10-05 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.953A>G at the cDNA level, p.Tyr318Cys (Y318C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). BMPR1A Tyr318Cys was identified in 1/46 healthy African-European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. BMPR1A Tyr318Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Tyrosine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BMPR1A Tyr318Cys occurs at a position that is conserved in mammals and is located in the protein kinase domain (Howe 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BMPR1A Tyr318Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120250 SCV000084400 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000120250 SCV000918663 uncertain significance not specified 2018-11-30 criteria provided, single submitter clinical testing Variant summary: BMPR1A c.953A>G (p.Tyr318Cys) results in a non-conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain of 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 2.8e-05 in 247208 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.953A>G has been reported in the literature in one individual affected with breast cancer. 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000410175 SCV000552880 uncertain significance Juvenile polyposis syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 318 of the BMPR1A protein (p.Tyr318Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. 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 not been reported in the literature in individuals with BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 127903). 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 tolerated, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120250 SCV000600232 uncertain significance not specified 2017-03-06 criteria provided, single submitter clinical testing

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