NM_004329.3(BMPR1A):c.858A>C (p.Glu286Asp) AND Juvenile polyposis syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003085730.5

Allele description [Variation Report for NM_004329.3(BMPR1A):c.858A>C (p.Glu286Asp)]

NM_004329.3(BMPR1A):c.858A>C (p.Glu286Asp)

Gene:

BMPR1A:bone morphogenetic protein receptor type 1A [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

10q23.2

Genomic location:

Preferred name:

NM_004329.3(BMPR1A):c.858A>C (p.Glu286Asp)

HGVS:

NC_000010.11:g.86917316A>C
NG_009362.1:g.165678A>C
NM_001406559.1:c.933A>C
NM_001406560.1:c.906A>C
NM_001406561.1:c.858A>C
NM_001406562.1:c.858A>C
NM_001406563.1:c.858A>C
NM_001406564.1:c.858A>C
NM_001406565.1:c.858A>C
NM_001406566.1:c.858A>C
NM_001406567.1:c.858A>C
NM_001406568.1:c.858A>C
NM_001406569.1:c.858A>C
NM_001406570.1:c.858A>C
NM_001406571.1:c.858A>C
NM_001406572.1:c.858A>C
NM_001406573.1:c.858A>C
NM_001406574.1:c.858A>C
NM_001406575.1:c.858A>C
NM_001406576.1:c.858A>C
NM_001406577.1:c.858A>C
NM_001406578.1:c.858A>C
NM_001406579.1:c.858A>C
NM_001406580.1:c.858A>C
NM_001406581.1:c.858A>C
NM_001406582.1:c.858A>C
NM_001406583.1:c.852A>C
NM_001406584.1:c.774A>C
NM_001406585.1:c.774A>C
NM_001406586.1:c.774A>C
NM_001406587.1:c.774A>C
NM_001406588.1:c.774A>C
NM_001406589.1:c.516A>C
NM_004329.3:c.858A>CMANE SELECT
NP_001393488.1:p.Glu311Asp
NP_001393489.1:p.Glu302Asp
NP_001393490.1:p.Glu286Asp
NP_001393491.1:p.Glu286Asp
NP_001393492.1:p.Glu286Asp
NP_001393493.1:p.Glu286Asp
NP_001393494.1:p.Glu286Asp
NP_001393495.1:p.Glu286Asp
NP_001393496.1:p.Glu286Asp
NP_001393497.1:p.Glu286Asp
NP_001393498.1:p.Glu286Asp
NP_001393499.1:p.Glu286Asp
NP_001393500.1:p.Glu286Asp
NP_001393501.1:p.Glu286Asp
NP_001393502.1:p.Glu286Asp
NP_001393503.1:p.Glu286Asp
NP_001393504.1:p.Glu286Asp
NP_001393505.1:p.Glu286Asp
NP_001393506.1:p.Glu286Asp
NP_001393507.1:p.Glu286Asp
NP_001393508.1:p.Glu286Asp
NP_001393509.1:p.Glu286Asp
NP_001393510.1:p.Glu286Asp
NP_001393511.1:p.Glu286Asp
NP_001393512.1:p.Glu284Asp
NP_001393513.1:p.Glu258Asp
NP_001393514.1:p.Glu258Asp
NP_001393515.1:p.Glu258Asp
NP_001393516.1:p.Glu258Asp
NP_001393517.1:p.Glu258Asp
NP_001393518.1:p.Glu172Asp
NP_004320.2:p.Glu286Asp
NP_004320.2:p.Glu286Asp
LRG_298t1:c.858A>C
LRG_298:g.165678A>C
LRG_298p1:p.Glu286Asp
NC_000010.10:g.88677073A>C
NM_004329.2:c.858A>C
NR_176211.1:n.1426A>C
NR_176212.1:n.1426A>C
NR_176213.1:n.1426A>C

Protein change:

E172D

Molecular consequence:

NM_001406559.1:c.933A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406560.1:c.906A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406561.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406562.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406563.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406564.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406565.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406566.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406567.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406568.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406569.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406570.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406571.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406572.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406573.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406574.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406575.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406576.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406577.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406578.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406579.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406580.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406581.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406582.1:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406583.1:c.852A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406584.1:c.774A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406585.1:c.774A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406586.1:c.774A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406587.1:c.774A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406588.1:c.774A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001406589.1:c.516A>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004329.3:c.858A>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Juvenile polyposis syndrome (JPS)
Synonyms:: Polyposis juvenile intestinal; Polyposis familial of entire gastrointestinal tract
Identifiers:: MONDO: MONDO:0017380; MedGen: C0345893; Orphanet: 2929; OMIM: 174900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003462330	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 4, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004831118	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Sep 17, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003462330

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 4, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004831118

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Sep 17, 2023)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	1	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003462330.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BMPR1A protein function. This variant has not been reported in the literature in individuals affected with BMPR1A-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 286 of the BMPR1A protein (p.Glu286Asp).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From All of Us Research Program, National Institutes of Health, SCV004831118.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (1)

Description

This missense variant replaces glutamic acid with aspartic acid at codon 286 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 not been reported in individuals affected with BMPR1A-related disorders in the literature. This variant has not been identified 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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