ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.98C>G (p.Thr33Ser) (rs142454490)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467157 SCV000552857 uncertain significance Juvenile polyposis syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 33 of the BMPR1A protein (p.Thr33Ser). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs142454490, ExAC 0.07%). This variant has not been reported in the literature in individuals with BMPR1A-related disease. ClinVar contains an entry for this variant (Variation ID: 411623). 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.
Ambry Genetics RCV000569418 SCV000668316 likely benign Hereditary cancer-predisposing syndrome 2018-11-26 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;Subpopulation frequency in support of benign classification
Color Health, Inc RCV000569418 SCV000682927 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-26 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355726 SCV001550684 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BMPR1A p.Thr33Ser variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (rs142454490) as “with other allele” and ClinVar (classified as uncertain significance by Invitae and Color and likely benign by Ambry Genetics). The variant was identified in control databases in 16 of 277,094 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 15 of 24,036 chromosomes (freq: 0.0006), Other in 1 of 6462 chromosomes (freq: 0.0002), but not in the Latino, Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The p.Thr33Ser residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.

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