NM_004329.2(BMPR1A):c.1A>C (p.Met1Leu) AND Hereditary cancer-predisposing syndrome

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: May 29, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_004329.2(BMPR1A):c.1A>C (p.Met1Leu)]

NM_004329.2(BMPR1A):c.1A>C (p.Met1Leu)

BMPR1A:bone morphogenetic protein receptor type 1A [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_004329.2(BMPR1A):c.1A>C (p.Met1Leu)
  • NC_000010.11:g.86876019A>C
  • NG_009362.1:g.124381A>C
  • NM_004329.2:c.1A>C
  • NP_004320.2:p.Met1Leu
  • LRG_298t1:c.1A>C
  • LRG_298:g.124381A>C
  • LRG_298p1:p.Met1Leu
  • NC_000010.10:g.88635776A>C
Protein change:
dbSNP: rs786203157
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_004329.2:c.1A>C - missense variant - [Sequence Ontology: SO:0001583]


Hereditary cancer-predisposing syndrome
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
MONDO: MONDO:0015356; MedGen: C0027672

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000581498Ambry Geneticscriteria provided, single submitter
(Oct 31, 2019)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001351393Color Health, Inccriteria provided, single submitter
Likely pathogenic
(May 29, 2020)
germlineclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis.

Calva-Cerqueira D, Chinnathambi S, Pechman B, Bair J, Larsen-Haidle J, Howe JR.

Clin Genet. 2009 Jan;75(1):79-85. doi: 10.1111/j.1399-0004.2008.01091.x. Epub 2008 Sep 24.

PubMed [citation]

BMPR1A mutations in juvenile polyposis affect cellular localization.

Howe JR, Dahdaleh FS, Carr JC, Wang D, Sherman SK, Howe JR.

J Surg Res. 2013 Oct;184(2):739-45. doi: 10.1016/j.jss.2013.01.015. Epub 2013 Feb 1.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000581498.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)


​The p.M1L pathogenic mutation (also known as c.1A>C) is located in coding exon 1 of the BMPR1A gene and results from an A to C substitution at nucleotide position 1. This changes the amino acid from a methionine to a leucine at the initiation codon. This mutation has been described in a patient with sporadic juvenile polyposis (Calva-Cerqueira D. et al. Clin Genet. 2009 Jan;75(1):79-85). Functional studies for this variant are conflicting with aberrant subcellular localization, intact bone morphogenetic protein (BMP) signaling, and reduced BMPR1A protein expression being demonstrated; however, BMPR1A protein may have failed to be detected due to a loss of the N-terminal portion of the protein with use of an alternate downstream start codon (Howe JR et al. J. Surg. Res., 2013 Oct;184:739-45). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV001351393.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)


This variant results in the loss of the translation start codon of the BMPR1A gene. The next in-frame methionine occurs at codon 29 that if used would delete the N-terminal signal peptide sequence (a.a. 1-23). The signal peptide motif is required for membrane-localization of the protein (PMID: 23433720). One study has shown that cells transfected with a construct containing this variant lacked the full-length BMPR1A protein product (PMID: 23433720). A protein product mislocalized to the cytoplasm was detected, but this study was inconclusive regarding the ability of the cytoplasmic protein to transduce BMP signaling. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD) and has been reported in an individual affected with juvenile polyposis (PMID: 18823382). Different variants that also result in the loss of p.Met1 have reported as disease-causing in ClinVar (variation ID: 186704, 224521, 653050, 824482, 843741), suggesting that this codon is important for protein expression and/or function. Loss of BMPR1A function is a known mechanism of disease. Based on the available evidence, this variant is classified as Likely Pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 19, 2021

Support Center