Submissions for variant NM_004329.3(BMPR1A):c.1333A>G (p.Ile445Val)

gnomAD frequency: 0.00002  dbSNP: rs587781503

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129478	SCV000184248	benign	Hereditary cancer-predisposing syndrome	2021-07-14	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	RCV000484454	SCV000566353	uncertain significance	not provided	2023-08-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with colorectal cancer (Yurgelun et al., 2017); This variant is associated with the following publications: (PMID: 28135145)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557878	SCV000632694	uncertain significance	Juvenile polyposis syndrome	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 445 of the BMPR1A protein (p.Ile445Val). This variant is present in population databases (rs587781503, gnomAD 0.01%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 141113). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt BMPR1A function with a negative predictive value of 95%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000129478	SCV000903823	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 445 of the BMPR1A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 6/251494 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	RCV000779844	SCV000916695	uncertain significance	not specified	2018-07-02	criteria provided, single submitter	clinical testing	Variant summary: BMPR1A c.1333A>G (p.Ile445Val) results in a conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain of the encoded protein sequence. Three of four in-silico tools predict a benign effect of the variant on protein function (MutationTaster not captured here due to low p-value). The variant allele was found at a frequency of 2.4e-05 in 246270 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1333A>G, has been reported in the literature in an individual affected with colorectal cancer (Yurgelun_2017). This report does not provide an unequivocal conclusion about association of the variant with Juvenile Polyposis Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submission from clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003474749	SCV004212632	uncertain significance	Polyposis syndrome, hereditary mixed, 2	2023-07-12	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000557878	SCV004836004	uncertain significance	Juvenile polyposis syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 445 of the BMPR1A protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 6/251494 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.