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 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
Population frequency
“
Absent from gnomAD v4.1.
“
Absent from gnomAD v2.1.
“
This variant is absent from gnomAD-Canada.
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.
Literature · 1 PMIDs triaged · 1 high-priority
1papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
25394175 ↗
case observation
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.
The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each pract
PP5PS4
Sources & reference links