NM_032043.3:c.2593C>T

BRIP1 · NP_114432.2:p.(Arg865Trp) · NM_032043.3

GRCh37: chr17:59763509 G>A · GRCh38: chr17:61686148 G>A

Gene: BRIP1 Transcript: NM_032043.3

Final call

VUS

PM2 supporting PP3 moderate

Variant details

Gene

BRIP1

Transcript

NM_032043.3

Protein

NP_114432.2:p.(Arg865Trp)

gnomAD AF

2.6642411745462117e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): variant is present but extremely rare in gnomAD (v4.1 total allele frequency 2.66e-05), below the 0.1% rarity threshold.

PP3 (Moderate): REVEL score 0.804 falls within the ClinGen-calibrated Pathogenic Moderate band (>=0.773).

PM2 (supporting) plus PP3 (moderate) satisfies no generic ACMG/AMP 2015 combining rule, so the variant is classified as VUS.

Final determination: Generic ACMG/AMP 2015 fallback combining rules require thresholds like (1 PS+1 PM), (3 PM), (2 PS) etc. for LP/P and (1 BS+1 BP)/(2 BP) for LB; 1 PM2-supporting + 1 PP3-moderate meets none, so VUS.

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	Not applicable: this missense substitution triggers no null-variant mechanism such as nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no alternate nucleotide change producing the identical p.Arg865Trp change with an established pathogenic classification was available.
PS2	Not assessed	Not assessed: no proband phenotype, parental genotypes, or parentage confirmation were available for this variant.	clinvar PMID:25741868
PS3	Not assessed	Not assessed: no validated functional assay data on this variant were found in any cited publication.
PS4	Not assessed	Not assessed: no case-control dataset reported carrier counts for this variant in affected individuals versus controls.	clinvar
PM1	Not met	Not met: Cancerhotspots.org returned no statistically significant hotspot at residue 865.	PMID:31822495
PM2	Met	Met (supporting): gnomAD v4.1 total allele frequency is 2.66e-05 (43/1,613,968), below the 0.1% PM2 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no affected individual carrying this variant together with a second pathogenic BRIP1 allele was reported.	clinvar
PM4	N/A	Not applicable: missense substitution produces no change in protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no alternate missense change at codon 865 with an established pathogenic classification was identified.
PM6	Not assessed	Not assessed: no report of this variant arising de novo in a proband with confirmed parental samples was available.	clinvar PMID:25741868
PP1	Not assessed	Not assessed: no evaluable family segregation data were available.	clinvar
PP2	Not assessed	Not assessed: missense is a recognized BRIP1 disease mechanism, but no missense constraint metric was available.	PMID:31822495
PP3	Met	Met (moderate): REVEL score 0.804 falls in the ClinGen-calibrated Pathogenic Moderate band (>=0.773).	revel
PP4	Not assessed	Not assessed: no proband phenotype data demonstrating specificity for a BRIP1-related disorder were available.
PP5	Not met	Not met: the ClinVar record lacks expert-panel submissions and is classified as uncertain significance by laboratory submitters.	clinvar
BA1	Not met	Not met: highest gnomAD v4.1 population allele frequency is 3.29e-05, far below the 5% BA1 threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: gnomAD allele frequencies (maximum 3.29e-05) are below the 0.3% BS1 threshold.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no phenotype- and age-ascertained observations of this variant in healthy adults were available.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no functional assay evidence of normal protein activity for this variant was found.
BS4	Not assessed	Not assessed: the reported lack of co-segregation in one family was insufficiently documented to establish non-segregation.	clinvar
BP1	Not met	Not met: BRIP1 missense variants are an established disease mechanism, so missense cannot be presumed benign.	PMID:31822495
BP2	Not assessed	Not assessed: no observation placed this variant in cis or trans with a pathogenic allele.	clinvar
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.804 falls in the pathogenic direction, so no benign in-silico evidence applies.	revel spliceai
BP5	Not assessed	Not assessed: no data established that the phenotype is explained by an alternative molecular diagnosis.
BP6	Not met	Not met: the ClinVar record has no expert-panel Benign/Likely benign assertion.	clinvar
BP7	N/A	Not applicable: this is a missense substitution, not a synonymous variant.	generic_acmg_combination_rules

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.