Variant classification summary

NM_032043.3:c.1372G>C

BRIP1 · NP_114432.2:p.(Glu458Gln) · NM_032043.3

GRCh37: chr17:59871059 C>G · GRCh38: chr17:61793698 C>G

Gene: BRIP1 Transcript: NM_032043.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

BRIP1

Transcript

NM_032043.3

Protein

NP_114432.2:p.(Glu458Gln)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_032043.3:c.1372G>C (p.Glu458Gln) is a missense variant in exon 10 of BRIP1.

2

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with PM2 (supporting).

3

Multiple computational tools predict no deleterious effect: REVEL score 0.334, BayesDel score -0.138785, and SpliceAI max delta 0.01, supporting BP4 (supporting).

4

No well-established functional studies have been performed for this variant; OncoKB reports unknown oncogenic effect (PS3 and BS3 not met).

5

ClinVar classifies this variant as Uncertain significance based on 2 clinical laboratory submissions (PS4, PP5 not met).

6

No segregation data, de novo observations, case-control studies, or variant-specific publications were identified for this variant.

7

This variant does not qualify as a null variant per ClinGen SVI PVS1 recommendations; PVS1 is not applicable.

8

The evidence yields PM2 (supporting) and BP4 (supporting), which effectively cancel each other. Based on the ACMG/AMP 2015 framework, this variant is classified as Uncertain significance.

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	Missense variant p.Glu458Gln does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 variant assessment confirms 'other' bucket; generic PVS1 framework is not applicable.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No known pathogenic variant at the same amino acid residue (E458) with a different missense change has been identified in ClinVar or the literature.	pm5_candidates
PS2	N/A	No de novo observation confirmed for NM_032043.3:c.1372G>C.
PS3	Not met	No well-established in vitro or in vivo functional studies have been performed for NM_032043.3:c.1372G>C (p.Glu458Gln). OncoKB reports unknown oncogenic effect with no variant-specific functional evidence. REVEL score of 0.334 is inconclusive.	oncokb revel
PS4	Not met	Variant has been observed in ClinVar as Uncertain significance (2 clinical laboratories) but no case-control data or statistically significant enrichment in affected individuals is available. PMID:25394175 is a general cancer referral guideline, not a variant-specific case-control study.	clinvar
PS5	N/A	Not a de novo variant with confirmed maternity and paternity; this criterion is reserved for established de novo observations.
PM1	N/A	Variant does not lie in a statistically significant mutational hotspot. Cancer Hotspots analysis is negative, and no critical functional domain without benign variation has been identified at this residue.
PM2	Met	NM_032043.3:c.1372G>C is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, indicating it is not present in large population cohorts. Allele frequency is below the 0.1% threshold for PM2 application.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No pathogenic comparator variant at the same amino acid residue (Glu458) identified. PM5 candidate search returned zero same-residue candidates.	pm5_candidates
PM6	N/A	No confirmed de novo observation for NM_032043.3:c.1372G>C with confirmed parentage.
PP1	N/A	No co-segregation data available for this variant.
PP2	Not met	While loss-of-function is a known disease mechanism in BRIP1, insufficient evidence exists that missense variants are a predominant mechanism of disease in this gene with a low rate of benign missense variation. No gene-specific missense constraint metric (e.g., missense Z-score) is available to support PP2.	pvs1_gene_context
PP3	Not met	Multiple computational tools do not support a deleterious effect. REVEL score is 0.334 (below the pathogenic threshold of 0.5). BayesDel score is -0.138785 (benign-leaning). SpliceAI max delta is 0.01 (no predicted splicing impact). The Ambry Genetics ClinVar submission notes: 'in silico prediction for this alteration is inconclusive.'	revel bayesdel spliceai clinvar
PP4	N/A	No patient phenotype data provided for this case; cannot assess whether the phenotype is specific for BRIP1-related disease.
PP5	Not met	ClinVar classification is Uncertain significance (2 clinical laboratories, criteria provided, single submitter), not a pathogenic classification from a reputable source. PMID:25394175 is a general cancer predisposition referral guideline and does not discuss NM_032043.3:c.1372G>C specifically.	clinvar
BA1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is well below the 1% threshold required for BA1.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from gnomAD. Allele frequency is not >0.3%, the threshold for BS1.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No evidence of homozygous occurrence or co-occurrence with a pathogenic variant in trans in a recessive gene.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies have been performed demonstrating no deleterious effect of NM_032043.3:c.1372G>C (p.Glu458Gln). OncoKB reports unknown oncogenic effect with no variant-specific functional annotation.	oncokb
BS4	Not met	No segregation data available to demonstrate lack of co-segregation with disease.
BP1	Not met	While loss-of-function is a known disease mechanism in BRIP1 (associated with Fanconi anemia and hereditary breast/ovarian cancer), pathogenic missense variants have been reported in this gene. Cannot conclude that only truncating variants cause disease in BRIP1, which is required for BP1 application.	pvs1_gene_context
BP2	N/A	No observation of this variant in trans with a known pathogenic variant in a dominant gene, or in cis with a known pathogenic variant.
BP3	N/A	Missense variant, not an in-frame deletion or insertion in a non-repeat region.
BP4	Met	Multiple lines of computational evidence suggest no deleterious impact. REVEL score is 0.334, BayesDel score is -0.138785 (negative/benign-leaning), and SpliceAI max delta score is 0.01 (no splicing impact). No computational tool predicts a pathogenic effect.	revel bayesdel spliceai
BP5	N/A	No alternative molecular basis for disease has been identified in this case.
BP6	Not met	This variant is not reported as benign or likely benign by a reputable source. ClinVar classification is Uncertain significance.	clinvar
BP7	N/A	Missense variant NM_032043.3:c.1372G>C (p.Glu458Gln), not synonymous. BP7 is reserved for synonymous variants with no predicted splicing impact.

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