Variant classification summary

NM_004329.3:c.398A>G

BMPR1A · NP_004320.2:p.(Tyr133Cys) · NM_004329.3

GRCh37: chr10:88659615 A>G · GRCh38: chr10:86899858 A>G

Gene: BMPR1A Transcript: NM_004329.3

Final call

VUS

PM2 supporting

Variant details

Gene

BMPR1A

Transcript

NM_004329.3

Protein

NP_004320.2:p.(Tyr133Cys)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting PM2 (supporting) for rarity.

3

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.

4

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.

5

No functional studies, de novo reports, cosegregation data, or case-control studies were identified for this specific variant.

6

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_004329.3:c.398A>G is a missense variant (NP_004320.2:p.Tyr133Cys) and does not fall into the null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus variants) required for PVS1 application under the ClinGen SVI PVS1 decision tree (PMC6185798).	pvs1_generic_framework
PS1	Not assessed	No alternative nucleotide change at codon 133 producing the same amino acid change (p.Tyr133Cys) was identified as a known pathogenic variant. Insufficient data to apply PS1.
PS2	Not met	No de novo occurrence data are available for NM_004329.3:c.398A>G. Targeted literature and database searches did not identify any report of this variant arising de novo with confirmed parentage.
PS3	Not assessed	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	Not met	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. The single ClinVar submission (Ambry Genetics, VUS) does not provide case-level prevalence data sufficient for PS4.	gnomad_v2 gnomad_v4 clinvar
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion. No applicable framework exists for this non-standard criterion.
PM1	Not assessed	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. Cancer Hotspots analysis shows no statistical significance at this residue.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	Not met	No known pathogenic missense variant at the same amino acid residue (Tyr133) was identified in ClinVar. The automated PM5 candidate search returned zero comparator variants. PM5 cannot be applied without a qualifying comparator.	pm5_candidates
PM6	Not met	No evidence of assumed de novo occurrence is available. No parental testing data or de novo case report was identified for NM_004329.3:c.398A>G.
PP1	Not met	No cosegregation data are available for NM_004329.3:c.398A>G with disease in multiple affected family members. Targeted literature search identified no family studies reporting this variant.
PP2	Not assessed	BMPR1A has pathogenic missense variants associated with disease (including non-truncating variants in familial colorectal cancer). However, no gene-specific missense constraint metric (e.g., Z-score, HCI prior probability) is available to determine whether the gene has a low rate of benign missense variation, which is a prerequisite for PP2 under generic ACMG/AMP rules.
PP3	Not met	REVEL score of 0.623 is moderately elevated above the 0.5 threshold, suggesting possible deleterious effect. However, BayesDel score of 0.073 does not reach the deleterious threshold (typically >0.13), and SpliceAI max delta score is 0.00, predicting no splice impact. Multiple lines of computational evidence do not reach consensus for a deleterious effect, which is required for PP3.	revel bayesdel spliceai
PP4	Not assessed	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	Not met	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). No reputable source has classified this variant as pathogenic. PMID:25394175 is a general practice guideline on cancer predisposition referral indications and does not report this specific variant as pathogenic.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data are available on observation of NM_004329.3:c.398A>G in healthy adults in the absence of BMPR1A-associated disease. The variant is absent from gnomAD, which precludes evaluation of healthy carrier frequency.
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on BMPR1A protein function were identified for this variant.
BS4	Not assessed	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	Not met	Missense variants are a recognized disease mechanism in BMPR1A. The gene context literature explicitly identifies non-truncating BMPR1A variants as associated with familial colorectal cancer and adenomatous polyps (PMID:41023686). Therefore, BP1, which applies only when truncating variants are the primary disease mechanism, is not met.
BP2	N/A	BMPR1A-related disorders (juvenile polyposis syndrome) follow autosomal dominant inheritance. Observation of this variant in trans with a pathogenic variant would require a homozygous state for a dominantly inherited condition, which is interpretively ambiguous and not standardly applied under BP2.
BP4	Not met	REVEL score of 0.623 is above the 0.5 threshold, suggesting possible deleterious effect rather than neutral impact. BayesDel score of 0.073 and SpliceAI max delta of 0.00 do not provide consensus support for a benign prediction. Multiple lines of computational evidence do not converge on a benign interpretation.	revel bayesdel spliceai
BP5	Not assessed	No data are available on an alternative molecular basis for disease in a patient harboring this variant. Without case-level information, BP5 cannot be assessed.
BP6	Not met	The ClinVar classification for NM_004329.3:c.398A>G (Variation ID 824461) is Uncertain Significance from a single clinical laboratory. No reputable source has classified this variant as benign.	clinvar
BP7	N/A	NM_004329.3:c.398A>G is a missense variant (p.Tyr133Cys) resulting in an amino acid substitution, not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.	spliceai

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