VCV000127902.29 - ClinVar

NM_004329.3(BMPR1A):c.676G>T (p.Val226Phe)

Germline

Classification

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.

(10)

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.

Conflicting classifications of pathogenicity
Uncertain significance(9); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004329.3(BMPR1A):c.676G>T (p.Val226Phe)

Variation ID: 127902 Accession: VCV000127902.29

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10q23.2 10: 86917134 (GRCh38) [ NCBI UCSC ] 10: 88676891 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Dec 6, 2016	Jun 17, 2024	Feb 19, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004329.3:c.676G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004320.2:p.Val226Phe	missense
NC_000010.11:g.86917134G>T
NC_000010.10:g.88676891G>T
NG_009362.1:g.165496G>T
LRG_298:g.165496G>T
LRG_298t1:c.676G>T	LRG_298p1:p.Val226Phe

... more HGVS ... less HGVS

Protein change

V226F

Other names

p.V226F:GTT>TTT

Canonical SPDI

NC_000010.11:86917133:G:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Exome Aggregation Consortium (ExAC) 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Links

ClinGen: CA288009 dbSNP: rs587780110 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help 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.
BMPR1A		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2329	2425

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 Help 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.
Hereditary cancer-predisposing syndrome	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Apr 5, 2023	RCV000561750.12
Generalized juvenile polyposis/juvenile polyposis coli Polyposis syndrome, hereditary mixed, 2	Uncertain significance (1)	criteria provided, single submitter	May 23, 2017	RCV000515164.2
Generalized juvenile polyposis/juvenile polyposis coli	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000123228.14
not provided	Uncertain significance (3)	criteria provided, multiple submitters, no conflicts	Jan 31, 2023	RCV000656784.6
Juvenile polyposis syndrome	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 11, 2024	RCV001293436.7
Polyposis syndrome, hereditary mixed, 2	Uncertain significance (1)	criteria provided, single submitter	Feb 19, 2024	RCV003474716.2

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.
Uncertain significance (Dec 15, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149738.16 First in ClinVar: May 17, 2014 Last updated: Dec 31, 2022	Comment: Observed in an individual with a personal history of adenomatous polyposis and papilla of Vater carcinoma, as well as a family history of colorectal cancer … (more) Observed in an individual with a personal history of adenomatous polyposis and papilla of Vater carcinoma, as well as a family history of colorectal cancer (Rosner et al., 2022); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9759503, 23433720, 36049049) (less)
Uncertain significance (Apr 05, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Color Diagnostics, LLC DBA Color Health Accession: SCV000682908.6 First in ClinVar: Feb 19, 2018 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 29596542‚ 36049049 Comment: This missense variant replaces valine with phenylalanine at codon 226 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces valine with phenylalanine at codon 226 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 29596542) and in an individual with polyposis (PMID: 36049049). This variant has been identified in 7/251294 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. (less)
Uncertain significance (Feb 19, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Polyposis syndrome, hereditary mixed, 2 Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004212612.2 First in ClinVar: Dec 30, 2023 Last updated: Jun 17, 2024
Uncertain significance (May 23, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Juvenile polyposis syndrome Polyposis syndrome, hereditary mixed, 2 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000611441.1 First in ClinVar: Nov 11, 2017 Last updated: Nov 11, 2017
Uncertain significance (Jan 13, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Juvenile polyposis syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001263367.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Uncertain significance (Jan 03, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV000600228.3 First in ClinVar: Dec 06, 2016 Last updated: Jan 06, 2024	Publications: PubMed (1) PubMed: 29596542 Comment: The frequency of this variant in the general population, 0.0006 (6/10078 chromosomes in Ashkenazi Jewish subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for … (more) The frequency of this variant in the general population, 0.0006 (6/10078 chromosomes in Ashkenazi Jewish subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported to co-occur with an MUTYH variant in an individual with colon cancer (PMID: 29596542 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Uncertain significance (Jan 09, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Juvenile polyposis syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000166534.13 First in ClinVar: Jun 15, 2014 Last updated: Feb 20, 2024	Publications: PubMed (2) PubMed: 28492532‚ 36049049 Comment: This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 226 of the BMPR1A protein (p.Val226Phe). … (more) This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 226 of the BMPR1A protein (p.Val226Phe). This variant is present in population databases (rs587780110, gnomAD 0.06%). This missense change has been observed in individual(s) with colorectal adenomas (PMID: 36049049). ClinVar contains an entry for this variant (Variation ID: 127902). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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. (less)
Uncertain Significance (Jan 11, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Juvenile polyposis syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004842878.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Publications: PubMed (2) PubMed: 29596542‚ 36049049 Comment: This missense variant replaces valine with phenylalanine at codon 226 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on … (more) This missense variant replaces valine with phenylalanine at codon 226 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 29596542) and in an individual with polyposis (PMID: 36049049). This variant has been identified in 7/251294 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. (less) Number of individuals with the variant: 10
Uncertain Significance (Jan 31, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV004848887.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024	Comment: The p.Val226Phe variant in BMPR1A has been reported in 1 individuals with adenomatous polyposis of the whole colon (Rosner 2022 PMID: 36049049). It has also … (more) The p.Val226Phe variant in BMPR1A has been reported in 1 individuals with adenomatous polyposis of the whole colon (Rosner 2022 PMID: 36049049). It has also been identified in 0.06% (2/3472) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3. (less)
Likely benign (Oct 07, 2022)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000668286.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely 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. (less)

Comment:

Observed in an individual with a personal history of adenomatous polyposis and papilla of Vater carcinoma, as well as a family history of colorectal cancer (Rosner et al., 2022); In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9759503, 23433720, 36049049)

Comment:

This missense variant replaces valine with phenylalanine at codon 226 of the BMPR1A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with colorectal cancer (PMID: 29596542) and in an individual with polyposis (PMID: 36049049). This variant has been identified in 7/251294 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.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

The frequency of this variant in the general population, 0.0006 (6/10078 chromosomes in Ashkenazi Jewish subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported to co-occur with an MUTYH variant in an individual with colon cancer (PMID: 29596542 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 226 of the BMPR1A protein (p.Val226Phe). This variant is present in population databases (rs587780110, gnomAD 0.06%). This missense change has been observed in individual(s) with colorectal adenomas (PMID: 36049049). ClinVar contains an entry for this variant (Variation ID: 127902). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.

Comment:

The p.Val226Phe variant in BMPR1A has been reported in 1 individuals with adenomatous polyposis of the whole colon (Rosner 2022 PMID: 36049049). It has also been identified in 0.06% (2/3472) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3.

Comment:

This alteration is classified as likely 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.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Adenomatous Polyposis Phenotype in BMPR1A and SMAD4 Variant Carriers.	Rosner G	Clinical and translational gastroenterology	2022	PMID: 36049049
Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer.	Hampel H	JAMA oncology	2018	PMID: 29596542

Text-mined citations for rs587780110 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_004329.3(BMPR1A):c.676G>T (p.Val226Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587780110 ...