ClinVar Miner

Submissions for variant NM_004329.2(BMPR1A):c.1327C>T (p.Arg443Cys) (rs35619497)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001507140 SCV000166528 benign Juvenile polyposis syndrome 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130683 SCV000185570 benign Hereditary cancer-predisposing syndrome 2014-12-09 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Co-occurence with mutation in same gene (phase unknown);Subpopulation frequency in support of benign classification
GeneDx RCV000120251 SCV000209877 likely benign not specified 2018-01-12 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.
Illumina Clinical Services Laboratory,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 uncertain significance not specified 2016-07-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586369 SCV000600214 benign not provided 2018-12-14 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
PreventionGenetics,PreventionGenetics RCV000586369 SCV000806597 uncertain significance not provided 2017-03-27 criteria provided, single submitter clinical testing
Color Health, Inc 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 Hereditary mixed polyposis syndrome 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]
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.
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.

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