NM_032043.3:c.254C>T

BRIP1 · NP_114432.2:p.(Ser85Leu) · NM_032043.3

GRCh37: chr17:59934544 G>A · GRCh38: chr17:61857183 G>A

Gene: BRIP1 Transcript: NM_032043.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

BRIP1

Transcript

NM_032043.3

Protein

NP_114432.2:p.(Ser85Leu)

gnomAD AF

9.913320404711306e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_032043.3:c.254C>T (p.Ser85Leu) is a missense variant in BRIP1. PVS1 does not apply as this is not a null variant.

This variant is present at extremely low frequency in population databases: gnomAD v2.1 at 0.00119% (3/251,440 alleles) and gnomAD v4.1 at 0.00099% (16/1,613,990 alleles), with no homozygotes observed. This meets the PM2 criterion at supporting strength for a rare variant in a gene associated with dominant cancer predisposition.

Multiple in silico prediction tools support a benign effect: REVEL score 0.078 (strongly benign-leaning), BayesDel score -0.316 (benign), and SpliceAI max delta 0.03 (no predicted splicing impact). These concordant predictions meet BP4 at supporting benign strength.

No functional studies have directly tested p.Ser85Leu. The largest BRIP1 missense functional characterization study (PMID:31822495) tested 20 helicase domain variants but did not include this residue. OncoKB reports no variant-specific functional evidence.

ClinVar classifies this variant as Uncertain Significance (Variation ID: 141545) with 1-star review status based on 14 clinical laboratory submissions. No expert panel classification is available. This does not meet criteria for PP5 or BP6 application.

No case-control studies, cosegregation data, de novo reports, or same-residue pathogenic comparators are available. BRIP1 missense variants in the helicase domain are a known disease mechanism (PMID:31822495), so BP1 does not apply despite this being a missense change.

The combined evidence (PM2 supporting + BP4 supporting benign) yields conflicting benign and pathogenic signals. The overall classification is Variant of Uncertain Significance (VUS), consistent with the ClinVar consensus.

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_032043.3:c.254C>T is a missense variant (p.Ser85Leu), not a null variant (nonsense, frameshift, or canonical splice site). PVS1 does not apply to missense substitutions under the ClinGen SVI PVS1 decision framework (PMC6185798).	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No different amino acid change at codon 85 has been established as pathogenic. PM5 candidate search found zero same-residue comparator variants in ClinVar.	pm5_candidates clinvar
PS2	Not met	No de novo occurrence of NM_032043.3:c.254C>T has been reported in any reviewed publication or ClinVar submission. Parental confirmation is absent.	clinvar
PS3	Not met	No functional studies have directly tested NM_032043.3:c.254C>T (p.Ser85Leu). The BRIP1 missense functional characterization study (PMID:31822495) tested 20 variants in the helicase domain but did not include p.Ser85Leu. No systematic range characterization (tiling screen, saturation mutagenesis) covers position 85. OncoKB reports no variant-specific functional evidence.	PMID:31822495 oncokb
PS4	Not met	No case-control studies demonstrate statistically significant enrichment of NM_032043.3:c.254C>T in affected individuals. The variant is observed in gnomAD at low frequency (3/251,440 alleles v2.1; 16/1,613,990 alleles v4.1), and no published prevalence data distinguish carrier frequency in cases versus controls.	gnomad_v2 gnomad_v4 clinvar
PS5	N/A	PS5 is not defined in the standard ACMG/AMP 2015 framework used for this generic assessment. No CSPEC/VCEP framework is available for BRIP1 that defines this criterion.	generic_acmg_combination_rules final_classification_framework
PM1	Not met	While p.Ser85Leu lies within the BRIP1 helicase domain (aa 1-888), a well-established functional domain, cancerhotspots.org does not identify this residue as a statistically significant mutational hotspot. The variant is present at very low frequency in population databases, and no domain-specific constraint or functional data demonstrate that position 85 is critical for protein function. Without a residue-specific hotspot or domain-level mutational constraint data, PM1 cannot be applied.	gnomad_v2 gnomad_v4 PMID:31822495
PM2	Met	NM_032043.3:c.254C>T is present at extremely low frequency in population databases: gnomAD v2.1 AF=1.19e-5 (3/251,440 alleles), gnomAD v4.1 AF=9.91e-6 (16/1,613,990 alleles), gnomAD-Canada absent. Both frequencies are well below the 0.1% PM2 threshold for a rare variant in a gene associated with dominant disease.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No different missense change at codon 85 has been classified as pathogenic in ClinVar. The PM5 candidate search returned zero same-residue comparator variants. PM5 requires a pathogenic missense variant at the same amino acid residue.	pm5_candidates clinvar
PM6	Not met	No de novo occurrence of NM_032043.3:c.254C>T has been reported, with or without confirmed parentage. No ClinVar submission asserts de novo origin.	clinvar
PP1	Not met	No cosegregation data are available for NM_032043.3:c.254C>T. No family studies with this variant have been published or included in ClinVar submissions.	clinvar
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. While BRIP1 missense variants can be pathogenic (PMID:31822495 demonstrated ~75% of tested helicase domain missense variants impair function), no gene-level constraint metric (e.g., missense Z-score, gnomAD constraint) was available to confirm a low rate of benign missense variation. HCI prior was not available for BRIP1.	PMID:31822495
PP3	Not met	Multiple in silico prediction tools support a benign effect for NM_032043.3:c.254C>T. REVEL score is 0.078 (well below the 0.5 threshold for pathogenicity). BayesDel score is -0.316 (negative score indicates benign). SpliceAI max delta is 0.03 (no predicted splicing impact). No computational evidence supports a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No specific patient phenotype or family history data are available to evaluate. BRIP1-associated cancer phenotypes (breast and ovarian cancer) are not highly specific for a single genetic etiology. Clinical testing submissions report this variant as VUS without phenotype specificity.	clinvar
PP5	Not met	ClinVar classifies NM_032043.3:c.254C>T as Uncertain Significance (Variation ID: 141545) with review status 'criteria provided, single submitter' (1 star). No expert panel (3-star) classification exists. PP5 requires a reputable source reporting the variant as pathogenic, which is not met.	clinvar
BA1	Not met	gnomAD allele frequency is 0.00119% (v2.1) and 0.00099% (v4.1), well below the 1% BA1 threshold. This variant is not common enough in population databases to be considered a benign polymorphism.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD allele frequency is 0.00119% (v2.1) and 0.00099% (v4.1), below the 0.3% BS1 threshold. The variant is too rare in population databases to apply BS1.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. While 3 alleles are observed in gnomAD v2.1 and 16 in v4.1, gnomAD does not confirm these individuals are healthy adults. Furthermore, BRIP1-associated cancer risk is adult-onset with moderate/incomplete penetrance, making the healthy-adult observation framework difficult to apply without explicit phenotype confirmation.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies demonstrate that NM_032043.3:c.254C>T (p.Ser85Leu) does not impair protein function. The BRIP1 functional study (PMID:31822495) tested 20 missense variants but did not include p.Ser85Leu. In silico predictors (REVEL 0.078, BayesDel -0.316) suggest a benign effect, but computational prediction alone is insufficient for BS3 which requires experimental functional evidence.	PMID:31822495 revel bayesdel
BS4	N/A	No family segregation data are available for this variant. BS4 requires observation of nonsegregation with disease in affected family members, which cannot be evaluated.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where primarily truncating variants cause disease. In BRIP1, missense variants in the helicase domain are a known disease mechanism: PMID:31822495 demonstrated that ~75% (15/20) of tested missense variants in the helicase domain significantly impair interstrand crosslink repair. Therefore, missense variation in BRIP1 cannot be assumed benign.	PMID:31822495
BP2	Not met	No evidence that NM_032043.3:c.254C>T has been observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. No such data are available.	clinvar
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without known function. NM_032043.3:c.254C>T is a missense substitution, not an in-frame indel.
BP4	Met	Multiple lines of computational evidence suggest NM_032043.3:c.254C>T does not impact gene product function. REVEL score is 0.078 (strongly benign-leaning, threshold for pathogenic is >0.5). BayesDel score is -0.316 (negative, indicating benign). SpliceAI max delta is 0.03 (no predicted splicing impact). These concordant predictions from independent algorithms support a benign interpretation.	revel bayesdel spliceai
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data are available for NM_032043.3:c.254C>T.	clinvar
BP6	Not met	ClinVar classifies NM_032043.3:c.254C>T as Uncertain Significance (Variation ID: 141545, 1-star review). BP6 requires a reputable source to report the variant as benign, which is not met.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splicing impact. NM_032043.3:c.254C>T is a missense variant (p.Ser85Leu), not a synonymous change.

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