Submissions for variant NM_004329.3(BMPR1A):c.1327C>T (p.Arg443Cys)

gnomAD frequency: 0.00081  dbSNP: rs35619497

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001507140	SCV000166528	benign	Juvenile polyposis syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000130683	SCV000185570	benign	Hereditary cancer-predisposing syndrome	2014-12-09	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.
GeneDx	RCV000586369	SCV000209877	likely benign	not provided	2021-01-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31968564, 28135145, 23399955, 25980754, 15235019, 12417513, 18823382, 28944238, 28873162, 27146957, 28660566, 25637381, 24728327, 24055113, 26976419, 23433720, 25058500, 21153778, 32522605)
Illumina Laboratory Services, Illumina	RCV000123222	SCV000365653	likely benign	Generalized juvenile polyposis/juvenile polyposis coli	2018-11-21	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000120251	SCV000593652	likely benign	not specified	2021-08-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586369	SCV000600214	benign	not provided	2023-02-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586369	SCV000698311	likely benign	not provided	2016-05-27	criteria provided, single submitter	clinical testing	Variant summary: The c.1327C>T in BMPR1A gene is a missense change that involves the alteration of a highly conserved nucleotide and 5/5 in silico tools predict deleterious outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.061%, predominantly in individuals of European and Latino origins (0.08% and 0.13%, respectively). These frequencies exceed the maximal expected allele frequency for a pathogenic variant in BMPR1A (0.0002%). The variant of interest has been reported via reputable database/clinical laboratories as VUS/Benign without evidence to independently evaluate. On the other hand, the variant was identified in JP pt, who reportedly carried a known germline pathogenic mutation in SMAD4 and functional studies showed that R443C expression and BMP signaling levels comparable to wild-type, but it was mislocalized in transfected cells. One other publication reports the variant to co-occur in a patient with a potential pathogenic MSH2 mutation, and an internal sample has a co-occurrence with a pathogenic PMS2 variant, c.2186_2187delTC (classified as pathogenic by LCA). Taken together, this variant has been classified as a Likely Benign.
Counsyl	RCV000123222	SCV000784746	likely benign	Generalized juvenile polyposis/juvenile polyposis coli	2017-12-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130683	SCV000910565	likely benign	Hereditary cancer-predisposing syndrome	2016-03-09	criteria provided, single submitter	clinical testing
Mendelics	RCV000123222	SCV001138112	benign	Generalized juvenile polyposis/juvenile polyposis coli	2019-05-28	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001292661	SCV001481263	uncertain significance	Polyposis syndrome, hereditary mixed, 2	2018-12-17	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as in patients with juvenile polyps as well as healthy controls [PMID 12417513, 25637381, 24728327, 24055113, 25058500, 23433720, 27146957, 23399955]
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000586369	SCV002009874	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130683	SCV002528563	benign	Hereditary cancer-predisposing syndrome	2020-03-20	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120251	SCV002549935	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001507140	SCV004019527	likely benign	Juvenile polyposis syndrome	2023-03-03	criteria provided, single submitter	clinical testing	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000586369	SCV004127022	likely benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	BMPR1A: PP3, BS1
ITMI	RCV000120251	SCV000084401	not provided	not specified	2013-09-19	no assertion provided	reference population
CSER _CC_NCGL, University of Washington	RCV000123222	SCV000190074	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli	2016-08-15	no assertion criteria provided	research	Originally interpreted based on literature review PMID: 25637381. Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 60 year old with over 20 adenomatous colon polyps and family history of colon cancer.
PreventionGenetics, part of Exact Sciences	RCV003891640	SCV000806597	likely benign	BMPR1A-related disorder	2020-09-25	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358272	SCV001553961	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The BMPR1A p.Arg443Cys variant was identified in 7 of 3226 proband chromosomes (frequency: 0.002) from individuals or families with juvenile polyposis, colorectal cancer and Lynch Syndrome, and was present in 1 of 1362 control chromosomes (frequency: 0.007) from healthy individuals (Sayed 2002, Jelsig 2016, Howe 2004, Calva-Cerqueira 2009, Esteban-Jurado 2014, Yurgelun 2015). The variant was identified in dbSNP (rs35619497) as “with other allele”, ClinVar (interpreted as "likely benign" by GeneDx and 4 others, "uncertain significance" by Genetic Services Laboratory and 3 others and "benign" by Invitae and 1 other) and LOVD 3.0 (observed 8x). The variant was identified in control databases in 175 of 277,254 chromosomes (1 homozygous) at a frequency of 0.0006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24,036 chromosomes (freq: 0.0002), Other in 7 of 6468 chromosomes (freq: 0.001), Latino in 58 of 34,420 chromosomes (freq: 0.002), European in 104 of 126,734 chromosomes (freq: 0.0008), Finnish in 2 of 25,794 chromosomes (freq: 0.00008), while the variant was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The variant was identified in an individual with a pathogenic MSH2 variant (c.1760-3G>C) (Yurgelun 2015). In HEK-293T cells transfected with the variant, BMPR1A protein was mislocalized, however protein expression and signaling were similar to wild type cells (Howe 2013). The p.Arg443 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.