Submissions for variant NM_004329.3(BMPR1A):c.33G>A (p.Leu11=)

gnomAD frequency: 0.00009  dbSNP: rs535411352

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001450063	SCV000261244	likely benign	Juvenile polyposis syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001080704	SCV000365643	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000421015	SCV000517093	likely benign	not specified	2018-01-20	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000575174	SCV000668297	likely benign	Hereditary cancer-predisposing syndrome	2015-08-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000575174	SCV000682884	likely benign	Hereditary cancer-predisposing syndrome	2017-03-08	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000421015	SCV000698315	benign	not specified	2023-06-29	criteria provided, single submitter	clinical testing	Variant summary: BMPR1A c.33G>A alters a conserved nucleotide resulting in a synonymous change. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.6e-05 in 150918 control chromosomes, predominantly at a frequency of 0.00079 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 400 fold of the estimated maximal expected allele frequency for a pathogenic variant in BMPR1A causing Juvenile Polyposis Syndrome phenotype (2e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.33G>A in individuals affected with Juvenile Polyposis Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=6) and VUS (n=2). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000588502	SCV000806603	likely benign	not provided	2017-07-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588502	SCV000888825	likely benign	not provided	2022-02-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000575174	SCV002528596	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-18	criteria provided, single submitter	curation