ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.749T>C (p.Met250Thr) (rs587780783)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000123229 SCV000166535 uncertain significance Juvenile polyposis syndrome 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 250 of the BMPR1A protein (p.Met250Thr). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and threonine. 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 suspected with Lynch syndrome (PMID: 25980754). It has also been observed in a homozygous individual unaffected by BMPR1A related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 136054). 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.
Ambry Genetics RCV000164314 SCV000214945 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000586264 SCV000567755 uncertain significance not provided 2015-08-20 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.749T>C at the cDNA level, p.Met250Thr (M250T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant was observed in a cohort of 1260 individuals with suspected Lynch syndrome that underwent panel testing for hereditary cancer risk (Yurgelun 2015). BMPR1A Met250Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BMPR1A Met250Thr occurs at a position that is conserved in mammals and is located in the MH1 domain, the cysteine-rich domain and the protein kinase domain (Howe 2004, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BMPR1A Met250Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586264 SCV000698325 likely benign not provided 2017-01-10 criteria provided, single submitter clinical testing Variant summary: The BMPR1A c.749T>C (p.Met250Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this substitution (SNPs&GO not captured due to low reliability index). This variant was found in 3/120980 control chromosomes, predominantly observed in the Latino subpopulation at a frequency of 0.0002603 (3/11526). This frequency greatly exceeds the estimated maximal expected allele frequency of a pathogenic BMPR1A variant (0.000002), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. In addition, in an internal sample, the variant was observed to co-occur with pathogenic BRCA1 variant further supporting neutrality. The variant was reported in one affected individual, however without strong evidence for causality such as co-segregation of the variant with the disease in multiple family members. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as likely benign.

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