ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.1235T>C (p.Val412Ala) (rs576247658)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000199134 SCV000254791 uncertain significance Juvenile polyposis syndrome 2019-01-09 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 412 of the BMPR1A protein (p.Val412Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs576247658, ExAC 0.02%). This variant has been reported in the literature in an individual with breast cancer (PMID: 25186627), and an individual with suspected Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 216576). 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. 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 RCV000213771 SCV000278427 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000199134 SCV000488212 uncertain significance Juvenile polyposis syndrome 2016-01-24 criteria provided, single submitter clinical testing
GeneDx RCV000589484 SCV000618141 uncertain significance not provided 2017-11-27 criteria provided, single submitter clinical testing This variant is denoted BMPR1A c.1235T>C at the cDNA level, p.Val412Ala (V412A) at the protein level, and results in the change of a Valine to an Alanine (GTG>GCG). This variant was reported in an individual undergoing multigene cancer panel testing due to a personal history of a Lynch syndrome-related cancer and/or polyps (Yurgelun 2015). BMPR1A Val412Ala was not observed at a significant frequency in large population cohorts (Lek 2016). Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. BMPR1A Val412Ala is located in the protein kinase domain (Howe 2004, UniProt). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether BMPR1A Val412Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color RCV000213771 SCV000682848 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589484 SCV000698307 likely benign not provided 2017-06-09 criteria provided, single submitter clinical testing Variant summary: The c.1235T>C (p.Val412Ala) in BPMR1A gene is a missense change that involves a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant of interest is located within the catalytic domain of the serine/threonine kinase, although the functional impact of this missense change is yet to be studied. The variant is present at a low frequency in large control population datasets of ExAC and gnomAD (0.000027; 3/121412 chrs tested and 0.00004; 12/277214 chrs tested, respectively) predominantly in individuals of African ancestry at frequencies that exceed the estimated maximal expected allele frequency of a pathogenic variant (0.000002). The variant has been reported in at least two affected individual (LS, BrC) via published reports and cited as VUS by a reputable database/diagnostic laboratory. In addition, the variant was identified in an unaffected individual undergoing genetic testing due to an extensive family history of BrC (three sisters and paternal aunt and 1st cousin). This individual also tested positive for a pathogenic mutation PMS2 c.2186_2187delTC p.L729fs*6 and likely pathogenic variant PALB2 c.801_802dupTA p.K268fs*12 (internal LCA data). Taken together, the variant was classified as Likely Benign until more data becomes available.

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