NM_032043.3:c.1171A>G

BRIP1 · NP_114432.2:p.(Ile391Val) · NM_032043.3

GRCh37: chr17:59876630 T>C · GRCh38: chr17:61799269 T>C

Gene: BRIP1 Transcript: NM_032043.3

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

BRIP1

Transcript

NM_032043.3

Protein

NP_114432.2:p.(Ile391Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRIP1 c.1171A>G (p.Ile391Val) variant has been reported in ClinVar and is currently classified there as a variant of uncertain significance with single-submitter review status.

This variant is very rare in population databases, with gnomAD v2.1 AF 3.99431e-06 (1/250356) and gnomAD v4.1 AF 4.95952e-06 (8/1613060), which are below the 0.1% PM2 threshold.

Computational data do not support a damaging effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.156, and BayesDel is -0.370746.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	This is a missense substitution, and the generic PVS1 assessment does not place it in a null-variant category such as nonsense, frameshift, or canonical +/-1,2 splice-site change. Although BRIP1 loss of function is an established disease mechanism, available evidence does not support applying PVS1 to c.1171A>G.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified that a different nucleotide change producing the same amino acid substitution, p.(Ile391Val), has already been established as pathogenic or likely pathogenic.
PS2	Not assessed	No confirmed de novo occurrence with established maternity and paternity was identified for this variant.
PS3	Not assessed	No well-established functional study showing a damaging effect of this specific variant was identified.	oncokb
PS4	Not assessed	This variant is reported in ClinVar, but available evidence does not provide exact case counts, case-control enrichment, or a statistically increased prevalence in affected individuals compared with controls.	clinvar
PM1	Not met	This variant does not lie in a statistically significant hotspot, and no evidence was identified that codon 391 is a well-established critical functional region without benign variation.	hotspots
PM2	Met	This variant is very rare in population databases. In gnomAD v2.1 the allele frequency is 3.99431e-06 (1/250356), and in gnomAD v4.1 the allele frequency is 4.95952e-06 (8/1613060) with grpmax FAF 3.472e-05; all are well below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed in trans with a pathogenic variant in a recessive disease context.
PM4	N/A	This is not a protein length-changing variant such as an in-frame insertion, in-frame deletion, or stop-loss variant.
PM5	Not assessed	No evidence was identified that another missense change at codon 391 has been established as pathogenic or likely pathogenic.
PM6	Not assessed	No presumed de novo occurrence was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant in affected relatives.
PP2	Not assessed	Available evidence does not establish that BRIP1 is a gene in which pathogenic missense variation is a common mechanism and benign missense variation is uncommon for this specific ACMG criterion.
PP3	Not met	Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.156, and BayesDel is -0.370746, which do not support pathogenic computational evidence for this missense change.	spliceai revel bayesdel
PP4	Not assessed	No highly specific phenotype or family history attributable to this exact variant was identified.
PP5	Not assessed	ClinVar lists this variant as uncertain significance with single-submitter review status, which does not provide a qualifying pathogenic reputable-source assertion for PP5.	clinvar
BA1	Not met	Population frequency does not meet the benign stand-alone threshold. The highest observed population value in the reviewed gnomAD data is far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not reach the benign strong threshold. The highest observed population frequency in the reviewed gnomAD data is 8.01047e-05 in gnomAD v4.1, which is well below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a manner sufficient for BS2 assessment.
BS3	Not assessed	No well-established functional study showing normal protein function for this specific variant was identified.	oncokb
BS4	Not assessed	No non-segregation data were identified for this variant.
BP1	Not assessed	This is a missense variant, but available evidence in the reviewed materials does not establish that BRIP1 disease is caused predominantly by truncating variants to the extent required for BP1 application.	pvs1_gene_context
BP2	Not assessed	No evidence was identified that this variant occurs in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant in a way that supports BP2.
BP3	N/A	This is not an in-frame insertion or deletion in a repetitive region.
BP4	Met	Multiple computational findings support no meaningful impact. SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, REVEL is 0.156, and BayesDel is -0.370746, which together support a benign computational interpretation rather than a damaging one.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular explanation was identified that would make this variant an incidental finding in the evaluated disease context.
BP6	Not assessed	No qualifying benign reputable-source assertion was identified. ClinVar reports this variant as uncertain significance rather than benign or likely benign.	clinvar
BP7	N/A	This is a missense variant, not a synonymous or deep intronic change, so BP7 does not apply.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.