Submissions for variant NM_004329.3(BMPR1A):c.1520A>G (p.Asn507Ser)

gnomAD frequency: 0.00006  dbSNP: rs750840234

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002229356	SCV000288388	uncertain significance	Juvenile polyposis syndrome	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 507 of the BMPR1A protein (p.Asn507Ser). This variant is present in population databases (rs750840234, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 30093976). ClinVar contains an entry for this variant (Variation ID: 239857). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is not expected to disrupt BMPR1A function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Counsyl	RCV000229682	SCV000489171	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2016-08-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563202	SCV000668315	benign	Hereditary cancer-predisposing syndrome	2022-06-03	criteria provided, single submitter	clinical testing	This alteration is classified as 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	RCV000563202	SCV000682875	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 507 of the BMPR1A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BMPR1A-related disorders in the literature. This variant has been identified in 6/282896 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000761117	SCV000891033	uncertain significance	B lymphoblastic leukemia lymphoma with t(12;21)(p13;q22); TEL-AML1 (ETV6-RUNX1)	2016-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV001589189	SCV001822397	uncertain significance	not provided	2023-02-23	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with breast cancer (Chan et al., 2018); This variant is associated with the following publications: (PMID: 25189415, 30093976)
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465590	SCV002760472	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002229356	SCV004019512	uncertain significance	Juvenile polyposis syndrome	2023-03-02	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003475079	SCV004210971	uncertain significance	Polyposis syndrome, hereditary mixed, 2	2023-10-04	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV002229356	SCV004838517	uncertain significance	Juvenile polyposis syndrome	2023-12-18	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 507 of the BMPR1A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/282896 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002465590	SCV005202339	uncertain significance	not specified	2024-07-29	criteria provided, single submitter	clinical testing	Variant summary: BMPR1A c.1520A>G (p.Asn507Ser) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251486 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1520A>G has been reported in the literature as a VUS in settings of multigene panel testing in at-least one individual affected with Breast cancer reporting no family history (example, Chan_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 30093976). ClinVar contains an entry for this variant (Variation ID: 239857). Based on the evidence outlined above, the variant was classified as uncertain significance.