ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.383A>G (p.Asn128Ser) (rs375165807)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166089 SCV000216854 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Invitae RCV000469945 SCV000552883 uncertain significance Juvenile polyposis syndrome 2018-11-23 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 128 of the BMPR1A protein (p.Asn128Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs375165807, ExAC 0.003%). This variant has been reported in an individual affected with tubular adenoma and hyperplastic polyps (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 186487). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
GeneDx RCV000479183 SCV000569008 uncertain significance not provided 2018-11-06 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.383A>G at the cDNA level, p.Asn128Ser (N128S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has been observed in at least one individual with rectal cancer and multiple polyps (Chubb 2015). BMPR1A Asn128Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Cysteine-rich domain (Kirsch 2000, Mahlawat 2012, Howe 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BMPR1A Asn128Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000166089 SCV000682889 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-15 criteria provided, single submitter clinical testing

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