Submissions for variant NM_004329.3(BMPR1A):c.760C>T (p.Arg254Cys)

gnomAD frequency: 0.00004  dbSNP: rs587782578

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131806	SCV000186861	likely benign	Hereditary cancer-predisposing syndrome	2019-02-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV001391326	SCV000254800	likely benign	Juvenile polyposis syndrome	2024-01-19	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131806	SCV000266155	uncertain significance	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000200056	SCV000488255	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2016-02-03	criteria provided, single submitter	clinical testing
GeneDx	RCV000484680	SCV000568872	uncertain significance	not provided	2023-08-22	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and/or family history or breast or colon cancer, as well as in unaffected controls in a study of biliary tract cancer (Selkirk et al., 2014; Tung et al., 2015; Shirts et al., 2016; Yurgelun et al., 2017; Rosner et al., 2022; Okawa et al., 2023); This variant is associated with the following publications: (PMID: 24755471, 25117502, 26845104, 28135145, 25186627, 36049049, 36243179)
Fulgent Genetics, Fulgent Genetics	RCV000515265	SCV000611442	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli; Polyposis syndrome, hereditary mixed, 2	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131806	SCV000682916	likely benign	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001731392	SCV001983574	likely benign	not specified	2021-09-04	criteria provided, single submitter	clinical testing	Variant summary: BMPR1A c.760C>T (p.Arg254Cys) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251296 control chromosomes. The observed variant frequency is approximately 28 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 benign. c.760C>T has been reported in the literature as a VUS in settings of multigene cancer panel testing in individuals affected with breast/colorectal cancer (example, Tung_2015, Yurgelun_2017). 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. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Baylor Genetics	RCV001788039	SCV002030103	uncertain significance	Polyposis syndrome, hereditary mixed, 2	2021-05-25	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Sema4, Sema4	RCV000131806	SCV002531118	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-04	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV001391326	SCV004019456	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000484680	SCV004222538	benign	not provided	2023-04-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905238	SCV004727480	uncertain significance	BMPR1A-related condition	2024-01-08	criteria provided, single submitter	clinical testing	The BMPR1A c.760C>T variant is predicted to result in the amino acid substitution p.Arg254Cys. This variant was reported in individuals with breast or colorectal cancer (Table S1, Selkirk et al. 2014. PubMed ID: 25117502; supporting information file 2, Tung et al. 2015. PubMed ID: 25186627; Table S1, Shirts et al. 2016. PubMed ID: 26845104; Yurgelun et al. 2017. PubMed ID: 28135145; Rosner et al. 2022. PubMed ID: 36049049). This variant is reported in 0.13% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142599/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.