NM_004329.3:c.398A>G (p.Tyr133Cys) is a missense variant in exon 6 of BMPR1A, a gene in which pathogenic variants cause juvenile polyposis syndrome and are associated with hereditary colorectal cancer. This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting PM2 (supporting) for rarity.1 REVEL in silico prediction (0.623) is moderately elevated, but BayesDel (0.073) and SpliceAI (max delta 0.00) do not agree with a deleterious interpretation; PP3 is not met.2 The ClinVar entry (Variation ID 824461) is classified as Uncertain Significance by a single clinical laboratory (Ambry Genetics); no reputable source has classified this variant as pathogenic or benign.3 No functional studies, de novo reports, cosegregation data, or case-control studies were identified for this specific variant. The only criterion met is PM2 (supporting); no pathogenic or benign criteria of higher strength are satisfied. Overall, the evidence is insufficient to classify this variant above or below VUS under the generic ACMG/AMP 2015 framework.4
BMPR1A
Final classification
VUS
BMPR1A c.398A>G · p.Tyr133Cys
BMPR1A
NM_004329.3:c.398A>G (p.Tyr133Cys) is a missense variant in exon 6 of BMPR1A, a gene in which pathogenic variants cause juvenile polyposis syndrome and are associated with hereditary colorectal cancer.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
BMPR1A c.398A>G
PM2
→
VUS
Gene diagram
· NM_004329.3 · variants mapped to exon structure
BMPR1A
NM_004329.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 21 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_004329.3:c.398A>G is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), meeting the PM2 criterion for a variant with allele frequency below 0.1% in large population cohorts.
Absent from gnomAD v2.1 (allele count 0)Absent from gnomAD v4.1 (allele count 0)
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change at codon 133 producing the same amino acid change (p.Tyr133Cys) was identified as a known pathogenic variant.
PS2
No de novo occurrence data are available for NM_004329.3:c.398A>G.
PS3
No well-established in vitro or in vivo functional studies demonstrating a damaging effect on BMPR1A function were identified for NM_004329.3:c.398A>G (p.Tyr133Cys).
PS4
The variant is absent from gnomAD population databases, but no case-control study has demonstrated statistically significant enrichment of NM_004329.3:c.398A>G in affected individuals versus controls.
PM1
Residue 133 is located in the extracellular ligand-binding domain of BMPR1A, but no VCEP-defined mutational hotspot or critical functional domain has been established for BMPR1A in the generic ACMG context.
PM5
No known pathogenic missense variant at the same amino acid residue (Tyr133) was identified in ClinVar.
PM6
No evidence of assumed de novo occurrence is available.
PP1
No cosegregation data are available for NM_004329.3:c.398A>G with disease in multiple affected family members.
PP2
BMPR1A has pathogenic missense variants associated with disease (including non-truncating variants in familial colorectal cancer).
PP3
REVEL score of 0.623 is moderately elevated above the 0.5 threshold, suggesting possible deleterious effect.
PP4
No patient phenotype or family history data are available to assess whether the clinical presentation is highly specific for BMPR1A-associated disease (juvenile polyposis syndrome or hereditary colorectal cancer).
PP5
The ClinVar entry for NM_004329.3:c.398A>G (Variation ID 824461) is classified as Uncertain Significance by a single clinical laboratory (Ambry Genetics).
Benign
BA1
NM_004329.3:c.398A>G is absent from gnomAD v2.1 and v4.1, yielding an allele frequency of 0%, which is far below the >1% threshold required for BA1.
BS1
The variant is absent from gnomAD v2.1 and v4.1, yielding an allele frequency of 0%, which is below the >0.3% threshold required for BS1.
BS2
No data are available on observation of NM_004329.3:c.398A>G in healthy adults in the absence of BMPR1A-associated disease.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect on BMPR1A protein function were identified for this variant.
BS4
No segregation data are available for NM_004329.3:c.398A>G to evaluate whether the variant fails to segregate with disease in affected families.
BP1
Missense variants are a recognized disease mechanism in BMPR1A.
BP4
REVEL score of 0.623 is above the 0.5 threshold, suggesting possible deleterious effect rather than neutral impact.
BP5
No data are available on an alternative molecular basis for disease in a patient harboring this variant.
BP6
The ClinVar classification for NM_004329.3:c.398A>G (Variation ID 824461) is Uncertain Significance from a single clinical laboratory.
N/A · 3
PVS1 · BP2 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 824461)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.623. BayesDel score = 0.0733129.
Functional
Unknown Oncogenic Effect
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
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 1 PMID not cited in assessment
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR