ClinVar Genomic variation as it relates to human health
NM_004329.3(BMPR1A):c.760C>T (p.Arg254Cys)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(8); Benign(1); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_004329.3(BMPR1A):c.760C>T (p.Arg254Cys)
Variation ID: 142599 Accession: VCV000142599.34
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q23.2 10: 86917218 (GRCh38) [ NCBI UCSC ] 10: 88676975 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Mar 20, 2016 Mar 16, 2024 Jan 19, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004329.3:c.760C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004320.2:p.Arg254Cys missense NC_000010.11:g.86917218C>T NC_000010.10:g.88676975C>T NG_009362.1:g.165580C>T LRG_298:g.165580C>T LRG_298t1:c.760C>T LRG_298p1:p.Arg254Cys - Protein change
- R254C
- Other names
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- Canonical SPDI
- NC_000010.11:86917217:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
Exome Aggregation Consortium (ExAC) 0.00003
The Genome Aggregation Database (gnomAD) 0.00004
The Genome Aggregation Database (gnomAD), exomes 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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BMPR1A | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
2245 | 2339 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Conflicting interpretations of pathogenicity (4) |
criteria provided, conflicting classifications
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Jan 4, 2024 | RCV000131806.18 | |
Uncertain significance (1) |
criteria provided, single submitter
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Feb 3, 2016 | RCV000200056.11 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Jan 19, 2024 | RCV001391326.8 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 4, 2021 | RCV001731392.1 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Aug 22, 2023 | RCV000484680.10 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 23, 2017 | RCV000515265.2 | |
Uncertain significance (1) |
criteria provided, single submitter
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Jan 8, 2024 | RCV003905238.1 | |
Uncertain significance (1) |
criteria provided, single submitter
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May 25, 2021 | RCV001788039.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Uncertain significance
(May 23, 2017)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis syndrome
Polyposis syndrome, hereditary mixed, 2
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000611442.1
First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017 |
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Uncertain significance
(May 25, 2021)
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criteria provided, single submitter
Method: clinical testing
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Polyposis syndrome, hereditary mixed, 2
Affected status: yes
Allele origin:
maternal
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Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV002030103.1 First in ClinVar: Dec 12, 2021 Last updated: Dec 12, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
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Likely benign
(Feb 09, 2019)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000186861.8
First in ClinVar: Aug 06, 2014 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: 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. (less)
Number of individuals with the variant: 1
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Uncertain significance
(Feb 03, 2016)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000488255.2
First in ClinVar: Jan 06, 2017 Last updated: Dec 24, 2022 |
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Uncertain significance
(Aug 22, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000568872.8
First in ClinVar: Apr 29, 2017 Last updated: Aug 31, 2023 |
Comment:
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and/or family history or … (more)
In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal and/or family history or breast or colon cancer, as well as in unaffected controls in a study of biliary tract cancer (Selkirk et al., 2014; Tung et al., 2015; Shirts et al., 2016; Yurgelun et al., 2017; Rosner et al., 2022; Okawa et al., 2023); This variant is associated with the following publications: (PMID: 24755471, 25117502, 26845104, 28135145, 25186627, 36049049, 36243179) (less)
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Benign
(Apr 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
unknown
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Quest Diagnostics Nichols Institute San Juan Capistrano
Accession: SCV004222538.1
First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024 |
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Likely benign
(Jan 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Color Diagnostics, LLC DBA Color Health
Accession: SCV000682916.5
First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024 |
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Likely benign
(Jan 19, 2024)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000254800.12
First in ClinVar: Oct 11, 2015 Last updated: Feb 28, 2024 |
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Uncertain significance
(Jan 08, 2024)
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criteria provided, single submitter
Method: clinical testing
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BMPR1A-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004727480.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The BMPR1A c.760C>T variant is predicted to result in the amino acid substitution p.Arg254Cys. This variant was reported in individuals with breast or colorectal cancer … (more)
The BMPR1A c.760C>T variant is predicted to result in the amino acid substitution p.Arg254Cys. This variant was reported in individuals with breast or colorectal cancer (Table S1, Selkirk et al. 2014. PubMed ID: 25117502; supporting information file 2, Tung et al. 2015. PubMed ID: 25186627; Table S1, Shirts et al. 2016. PubMed ID: 26845104; Yurgelun et al. 2017. PubMed ID: 28135145; Rosner et al. 2022. PubMed ID: 36049049). This variant is reported in 0.13% of alleles in individuals of Ashkenazi Jewish descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/142599/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
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Uncertain significance
(Nov 20, 2015)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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University of Washington Department of Laboratory Medicine, University of Washington
Accession: SCV000266155.1
First in ClinVar: Mar 20, 2016 Last updated: Mar 20, 2016 |
Number of individuals with the variant: 1
Clinical Features:
breast cancer (present)
Age: 40-49 years
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Likely benign
(Sep 04, 2021)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV001983574.1
First in ClinVar: Oct 30, 2021 Last updated: Oct 30, 2021 |
Comment:
Variant summary: BMPR1A c.760C>T (p.Arg254Cys) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four … (more)
Variant summary: BMPR1A c.760C>T (p.Arg254Cys) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251296 control chromosomes. The observed variant frequency is approximately 28 fold of the estimated maximal expected allele frequency for a pathogenic variant in BMPR1A causing Juvenile Polyposis Syndrome phenotype (2e-06), strongly suggesting that the variant is benign. c.760C>T has been reported in the literature as a VUS in settings of multigene cancer panel testing in individuals affected with breast/colorectal cancer (example, Tung_2015, Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Juvenile Polyposis Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign. (less)
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Uncertain significance
(Mar 04, 2022)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
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Sema4, Sema4
Accession: SCV002531118.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
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Uncertain significance
(Mar 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Juvenile polyposis syndrome
Affected status: unknown
Allele origin:
unknown
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Myriad Genetics, Inc.
Accession: SCV004019456.1
First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023 |
Comment:
This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. | Yurgelun MB | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2017 | PMID: 28135145 |
Improving performance of multigene panels for genomic analysis of cancer predisposition. | Shirts BH | Genetics in medicine : official journal of the American College of Medical Genetics | 2016 | PMID: 26845104 |
Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. | Tung N | Cancer | 2015 | PMID: 25186627 |
Cancer genetic testing panels for inherited cancer susceptibility: the clinical experience of a large adult genetics practice. | Selkirk CG | Familial cancer | 2014 | PMID: 25117502 |
BMPR1A mutations in juvenile polyposis affect cellular localization. | Howe JR | The Journal of surgical research | 2013 | PMID: 23433720 |
The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. | Calva-Cerqueira D | Clinical genetics | 2009 | PMID: 18823382 |
Text-mined citations for rs587782578 ...
HelpRecord last updated Mar 17, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.