ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.499A>G (p.Met167Val) (rs200951235)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168197 SCV000218862 uncertain significance Juvenile polyposis syndrome 2018-11-25 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 167 of the BMPR1A protein (p.Met167Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs200951235, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145, 25980754), and an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 188242). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this sequence change is likely to be tolerated, but these predictions have not been confirmed by published functional 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 RCV000254949 SCV000321418 uncertain significance not provided 2018-09-20 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.499A>G at the cDNA level, p.Met167Val (M167V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been identified in at least one individual with colorectal cancer and in individuals with breast and/or ovarian cancer (Tung 2015, Yurgelun 2015, Maxwell 2016, Yurgelun 2017). BMPR1A Met167Val was observed at an allele frequency of 0.02% (4/24026) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Met167Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000493778 SCV000581485 likely benign Hereditary cancer-predisposing syndrome 2017-08-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,In silico models in agreement (benign)
Color RCV000493778 SCV000682897 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
Counsyl RCV000168197 SCV000786602 uncertain significance Juvenile polyposis syndrome 2018-06-05 criteria provided, single submitter clinical testing
GeneKor MSA RCV000493778 SCV000821914 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing

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