The BMPR1A NM_004329.3:c.1420G>C (NP_004320.2:p.(Val474Leu)) missense variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.BMPR1A is a cell-surface receptor that helps transmit bone morphogenetic protein signals, regulating cell growth, specialization, death, bone formation, and fat-cell development. Inherited BMPR1A defects are associated with juvenile polyposis syndrome and Cowden syndrome, which can cause gastrointestinal polyps. BMPR1A acts as a tumor suppressor, and inherited defects increase the risk of gastrointestinal and colorectal cancer.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at supporting strength: gnomAD v4.1 grpmax FAF is 0.00008424, below the <=0.0001 PM2 threshold.
No benign criterion marked as applied in the recorded assessment.
VUS: PM2 (supporting) is the only applied criterion and does not satisfy any generic ACMG/AMP pathogenic, likely pathogenic, benign, or likely benign combination.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 124 / 1,614,240 alleles. Recorded AF 7.68163e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 4.24184e-05; MAF= 0.00424%, 12/282896 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.01025e-05; MAF= 0.00801%, 2/24968 alleles, homozygotes = 0); grpmax FAF= 4.113e-05.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.454. Refer to the recorded PP3/BP4 rationale for interpretation.
10 Uncertain significance · 1 Benign · 1 Likely benign · 1 Uncertain Significance. ClinVar API review status: criteria provided, conflicting classifications.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BMPR1A, a transmembrane receptor kinase, is frequently altered by mutation and deletion in various cancers, including colorectal and endometrial cance
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 9 not met · 14 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No proband-level de novo, parental-testing, segregation, or non-segregation evidence was available for PS2, PM6, PP1, or BS4; all four criteria are not assessed.
No VCEP covers BMPR1A in this case; generic ACMG/AMP 2015 rules govern.
The exact variant is NM_004329.3:c.1420G>C (NP_004320.2:p.Val474Leu).
The available literature does not provide exact-variant case-control, phenotype-specific, alternate-molecular-basis, or qualifying expert-panel evidence for these five criteria.
No criteria match.
PM2 is met at supporting strength. The supplied generic SVI threshold permits extremely low frequency at <=0.0001. The all-comers gnomAD v4.1 grpmax FAF is 8.424e-05 and the all-comers gnomAD v2.1 grpmax FAF is 4.113e-05, both below that threshold; the variant is present at very low frequency rather than completely absent. No governing VCEP specifies a non-cancer or exome-only source, so the all-comers entries are the applicable default. The non-cancer subsets are concordant, with v2.1 exomes grpmax FAF=3.126e-05 and v3.1 genomes grpmax FAF=1.972e-05.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
The variant is BMPR1A p.Val474Leu (NM_004329.3:c.1420G>C). The available exact-variant literature extraction reports no publication of this variant and no established pathogenic variant producing the same amino-acid change. ClinVar contains conflicting submissions for the exact variant, including uncertain significance, benign, and likely benign, with no expert-panel pathogenic classification. Therefore, the PS1 requirement for a previously established pathogenic variant causing the same amino-acid change is not met.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
The governing ACMG/AMP definition requires a significantly increased prevalence in affected individuals compared with controls, with OR or RR >5.0 and a confidence interval excluding 1.0. The reviewed literature does not report this exact BMPR1A c.1420G>C (p.Val474Leu) variant in affected individuals or controls, and provides no case-control counts, case frequency, odds ratio, or confidence interval. PMID:25980754 included BMPR1A on a multigene panel but did not report this variant or any BMPR1A-positive cohort result; the other screened papers likewise did not provide variant-specific case-control evidence. Therefore no qualifying PS4 evidence is present.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
The variant is BMPR1A p.Val474Leu. No different missense change at residue Val474 has been established as pathogenic in the supplied evidence. The exact-variant ClinVar record is conflicting and includes uncertain-significance, benign, and likely-benign classifications; the available literature extraction does not report p.Val474Leu or a qualifying same-residue pathogenic comparator. Therefore, the PM5 requirement is not met.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
The variant is a missense substitution, NM_004329.3:c.1420G>C (p.Val474Leu), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3 in this situation. REVEL is 0.454, below the published generic PP3 supporting threshold of >=0.644 (and therefore also below the moderate threshold of >=0.773 and strong threshold of >=0.932) from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). The applicable computational evidence does not meet PP3.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The governing rule requires a reputable source to recently report the exact variant as pathogenic when the evidence is unavailable for independent evaluation. Exact-match ClinVar records for NM_004329.3:c.1420G>C include no expert-panel submission and no Pathogenic or Likely pathogenic expert-panel classification; the submissions are conflicting, consisting primarily of uncertain significance with one benign and one likely benign clinical-laboratory submission. The literature reviewed also does not report this exact variant as pathogenic. Ordinary laboratory submissions and aggregate ClinVar labels do not satisfy the required PP5 trigger.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. The required filtering population frequency is gnomAD grpmax FAF, not the popmax point estimate. The all-comers gnomAD v2.1 grpmax FAF is 4.113e-05 and the all-comers gnomAD v4.1 grpmax FAF is 8.424e-05; both are far below the generic stand-alone threshold of 0.05. The highest observed v4.1 population point estimate, 9.91493e-05 in European (non-Finnish) individuals, is not used for BA1, and the variant has no frequency evidence approaching 5%. No VCEP requires a non-cancer or exome-only source, so the all-comers totals are the applicable default.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met. The required filtering population frequency is gnomAD grpmax FAF. The all-comers gnomAD v2.1 grpmax FAF is 4.113e-05 and the all-comers gnomAD v4.1 grpmax FAF is 8.424e-05, both below the supplied generic default threshold of 0.01. The v4.1 population with the highest point estimate has 1,180,038 observed alleles, exceeding the 2,000-allele reliability requirement, but its filtering FAF still remains far below 0.01. A disorder-specific maximum-credible-frequency calculation is unnecessary to resolve this result because the observed filtering frequencies are over two orders of magnitude below the generic threshold.
BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
The variant is a missense substitution, NM_004329.3:c.1420G>C (p.Val474Leu), so the governing generic rule selects the REVEL path only; SpliceAI is not used to support BP4 for a missense variant. REVEL is 0.454, above the generic BP4 supporting upper threshold of <=0.29 (and above the moderate <=0.183 and strong <=0.016 thresholds) from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). The REVEL result is therefore not supportive of BP4; the SpliceAI max delta of 0.015 is not applicable to this missense BP4 assessment.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
The governing rule requires a reputable source to recently report the exact variant as benign when the evidence is unavailable for independent evaluation. The exact-match ClinVar record has no expert-panel submission; its benign and likely benign classifications are ordinary single clinical-laboratory submissions, while the aggregate record is conflicting and predominantly uncertain significance. Under the specified generic rule, these non-expert assertions cannot trigger BP6.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
No case-level evidence establishes that NM_004329.3:c.1420G>C occurred de novo in a proband with the relevant disease. The available records do not document the proband's phenotype, family history, testing of both biological parents, or confirmed maternity and paternity; therefore PS2 cannot be assessed.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No variant-specific, validated functional assay demonstrating a damaging effect was identified for BMPR1A NM_004329.3:c.1420G>C (p.Val474Leu). The reviewed literature does not report this variant or functional assay results, and OncoKB reports no variant-specific reviewed functional evidence. Therefore, the evidence is insufficient to assess PS3 rather than supporting or refuting it.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
BMPR1A p.Val474Leu is a missense variant, and the available material includes a non-authoritative annotation that the variant is located in an annotated protein kinase domain. However, no VCEP specification or authoritative domain table is available for BMPR1A, and the supplied evidence does not establish that the relevant domain is a well-established critical functional domain for this criterion without benign variation. The generic PM1 evidence requirement therefore cannot be confirmed from the available evidence.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The generic PM3 definition applies only to recessive disorders and requires the variant to be detected in trans with a pathogenic variant, with parental or offspring testing to establish phase. The available case evidence identifies BMPR1A-associated juvenile polyposis syndrome but does not document the disorder's inheritance mode for this assessment, a pathogenic allele in the same proband, affected-proband observations, or parent/offspring phase testing. Therefore PM3 cannot be assessed.
For recessive disorders, detected in trans with a pathogenic variant...This requires testing of parents (or offspring) to determine phase.
No case-level evidence describes an assumed de novo occurrence of NM_004329.3:c.1420G>C. The available records do not report a proband phenotype, family history, or parental testing from which an assumed de novo event could be established; therefore PM6 cannot be assessed.
Assumed de novo, but without confirmation of paternity and maternity.
No variant-specific pedigree or testing data show co-segregation of NM_004329.3:c.1420G>C with disease in affected family members. The available records do not identify affected relatives, their phenotypes, their variant genotypes, or the number of informative meioses; therefore PP1 cannot be assessed.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... May be used as stronger evidence with increasing segregation data.
The available evidence supports BMPR1A loss of function as a disease mechanism and identifies a paper focused on non-truncating BMPR1A variants, but it does not provide the gene-level benign missense rate or establish that missense variants are a common disease mechanism under the PP2 definition. The required two-part gene-level evidence is therefore insufficient for assessment.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The governing rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The supplied case evidence identifies BMPR1A c.1420G>C (p.Val474Leu) and disease contexts in ClinVar, but does not provide the patient's phenotype, family history, or a documented highly specific juvenile polyposis phenotype. The criterion cannot be assessed from the available patient-level evidence.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 is not assessed because the available population data do not document this variant in a specifically identified healthy adult individual. gnomAD reports zero homozygotes in both v2.1 and v4.1, but aggregate allele counts do not establish a healthy adult heterozygote, the individual's age, phenotype, or the penetrance needed for the BS2 definition. No supplied source provides an individual-level healthy-adult observation for BMPR1A c.1420G>C (p.Val474Leu).
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No variant-specific, validated functional assay demonstrating absence of a damaging effect on BMPR1A protein function or splicing was identified for NM_004329.3:c.1420G>C (p.Val474Leu). The reviewed literature does not report this variant or functional assay results, and OncoKB reports no variant-specific reviewed functional evidence. Therefore, the evidence is insufficient to assess BS3 rather than supporting or refuting it.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
No variant-specific family data demonstrate that NM_004329.3:c.1420G>C fails to segregate with disease in affected relatives. The available records do not identify affected relatives who were tested negative, and there is no information to evaluate phenocopies or the possibility of more than one pathogenic variant in the family; therefore BS4 cannot be assessed.
Lack of segregation in affected members of a family.
The available evidence supports BMPR1A loss of function as a disease mechanism, but it does not establish that BMPR1A disease is caused primarily by truncating variants. The available literature also includes non-truncating BMPR1A variants associated with familial colorectal cancer and adenomatous polyps, so the required gene-level predominance cannot be inferred. BP1 is therefore not assessable from the supplied evidence.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 requires an observation in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or an observation in cis with a pathogenic variant in any inheritance pattern. The available evidence contains no affected-proband or other individual-level co-occurrence observation for NM_004329.3:c.1420G>C, no pathogenic variant paired with it, and no phase result establishing cis or trans. Therefore BP2 cannot be assessed.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The governing rule requires the variant to be found in a case with an alternate molecular basis for disease. The available records do not document a case-level alternate pathogenic molecular diagnosis, a second causal variant, or a disease mechanism that explains the patient's phenotype independently of BMPR1A. ClinVar condition labels and population observations do not establish BP5.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_004329.3:c.1420G>C in BMPR1A is a missense substitution predicted to produce NP_004320.2:p.(Val474Leu). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for BMPR1A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_004329.3:c.1420G>C in BMPR1A is a missense substitution predicted to produce NP_004320.2:p.(Val474Leu). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for BMPR1A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_004329.3:c.1420G>C in BMPR1A is a missense substitution predicted to produce NP_004320.2:p.(Val474Leu). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for BMPR1A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_004329.3:c.1420G>C in BMPR1A is a missense substitution predicted to produce NP_004320.2:p.(Val474Leu). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for BMPR1A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in BMPR1A, mapped onto the exon structure of NM_004329.3. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)117 / 1,180,038 | 9.9e-05 |
| Remaining individuals4 / 62,512 | 6.4e-05 |
| African/African American3 / 75,060 | 4e-05 |
| African/African American2 / 24,968 | 8e-05 |
| European (non-Finnish)10 / 129,198 | 7.7e-05 |
This variant is present in gnomAD v4.1 (AF= 7.68163e-05; MAF= 0.00768%, 124/1614240 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.91493e-05; MAF= 0.00991%, 117/1180038 alleles, homozygotes = 0); grpmax FAF= 8.424e-05.
This variant is present in gnomAD v2.1 (AF= 4.24184e-05; MAF= 0.00424%, 12/282896 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.01025e-05; MAF= 0.00801%, 2/24968 alleles, homozygotes = 0); grpmax FAF= 4.113e-05.
Not available in gnomAD-Canada v1.0.
The variant is a missense substitution, NM_004329.3:c.1420G>C (p.Val474Leu), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3 in this situation. REVEL is 0.454, below the published generic PP3 supporting threshold of >=0.644 (and therefore also below the moderate threshold of >=0.773 and strong threshold of >=0.932) from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). The applicable computational evidence does not meet PP3.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
The variant is a missense substitution, NM_004329.3:c.1420G>C (p.Val474Leu), so the governing generic rule selects the REVEL path only; SpliceAI is not used to support BP4 for a missense variant. REVEL is 0.454, above the generic BP4 supporting upper threshold of <=0.29 (and above the moderate <=0.183 and strong <=0.016 thresholds) from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). The REVEL result is therefore not supportive of BP4; the SpliceAI max delta of 0.015 is not applicable to this missense BP4 assessment.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_004329.3:c.1420G>C in BMPR1A is a missense substitution predicted to produce NP_004320.2:p.(Val474Leu). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for BMPR1A, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.454. BayesDel score = 0.0267105.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
The variant classification approach described in this paper is meant to be applicable to variants in all Mendelian genes whether identified by single gene tests, multi-gene panels, exome sequencing or genome sequencing.
Proposed Criteria for Interpretation of Sequence Variants, introductory paragraph
Hamartomatous polyps, increased risk for colorectal, pancreatic, gastric and duodenal cancer
Table I, p. 87, entry for Juvenile polyposis syndrome
The genes underlying LS, adenomatous polyposis (APC and MUTYH) and hamartomatous polyposis (BMPR1A, PTEN, SMAD4, and STK11) syndromes, BRCA1/2, familial atypical multiple mole melanoma syndrome (CDKN2A and CDK4), hereditary diffuse gastric cancer (CDH1), and Li-Fraumeni syndrome (TP53) were categorized as high-penetrance
Methods, Germline Sequencing/Interpretation
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 7.68163e-05; MAF= 0.00768%, 124/1614240 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.91493e-05; MAF= 0.00991%, 117/1180038 alleles, homozygotes = 0); grpmax FAF= 8.424e-05.
This variant is present in gnomAD v2.1 (AF= 4.24184e-05; MAF= 0.00424%, 12/282896 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.01025e-05; MAF= 0.00801%, 2/24968 alleles, homozygotes = 0); grpmax FAF= 4.113e-05.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Uncertain significance (10 clinical laboratories) and as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 141060)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.454. BayesDel score = 0.0267105.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BMPR1A, a transmembrane receptor kinase, is frequently altered by mutation and deletion in various cancers, including colorectal and endometrial cance
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.