NM_032043.3:c.143C>A

BRIP1 · NP_114432.2:p.(Thr48Lys) · NM_032043.3

GRCh37: chr17:59937219 G>T · GRCh38: chr17:61859858 G>T

Gene: BRIP1 Transcript: NM_032043.3

Final call

VUS

PM2 supporting PP3 supporting BP1 supporting benign

Variant details

Gene

BRIP1

Transcript

NM_032043.3

Protein

NP_114432.2:p.(Thr48Lys)

gnomAD AF

3.7178637155090683e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_032043.3:c.143C>A (p.Thr48Lys) is a missense variant in BRIP1, a moderate-penetrance breast and ovarian cancer predisposition gene where the predominant disease mechanism is protein truncation.

This variant is extremely rare in population databases: gnomAD v2.1 allele frequency is 0.00319% (1/31,388 alleles) and v4.1 allele frequency is 0.00037% (6/1,613,830 alleles) with no homozygotes observed, meeting PM2 at supporting strength.

In silico analysis supports a deleterious effect: REVEL score of 0.728 exceeds the 0.7 threshold for damaging prediction; the Thr48Lys substitution is non-conservative, replacing a polar uncharged residue with a positively charged one, meeting PP3 at supporting strength.

BRIP1 disease-causing mutations predominantly result in protein truncation or nonsense-mediated RNA decay. This missense variant is not consistent with the primary disease mechanism, meeting BP1 at supporting benign strength.

This variant has been reported in ClinVar as Uncertain significance by 5 clinical laboratories (Variation ID 234642, 1-star review status). No functional studies, segregation data, de novo observations, or case-control data are available.

No functional studies or literature directly testing NM_032043.3:c.143C>A (p.Thr48Lys) or a systematically characterized residue range including position 48 were identified. The variant has not been reported in COSMIC and OncoKB reports Unknown Oncogenic Effect.

The evidence profile includes one pathogenic supporting criterion (PM2), one pathogenic supporting criterion (PP3), and one benign supporting criterion (BP1), resulting in net neutral evidence. Based on generic ACMG/AMP 2015 combination rules, this variant is classified as a Variant of 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	Not met	NM_032043.3:c.143C>A is a missense variant (p.Thr48Lys) in BRIP1 exon 3. It does not fall into any default PVS1 null-variant category (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 decision tree per ClinGen SVI recommendations (PMC6185798) does not apply to missense variants.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence of a different nucleotide change at codon 48 (same amino acid change p.Thr48Lys) that has been reported as pathogenic in the literature or databases.
PS2	Not met	No de novo occurrence data (with confirmed maternity and paternity) available for NM_032043.3:c.143C>A.
PS3	Not met	No functional studies were identified that directly tested NM_032043.3:c.143C>A (p.Thr48Lys) or a systematically characterized residue range that includes position 48. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. The full-text literature review did not identify any experimental functional data for this variant.	oncokb
PS4	Not met	No case-control studies or cohort data establishing statistically significant enrichment of NM_032043.3:c.143C>A in affected individuals versus controls are available. The variant is reported in ClinVar as Uncertain significance by 5 clinical laboratories without prevalence data.	clinvar
PS5	Not met	No pathogenic variant at codon 48 has been reported through non-ClinVar (literature-based) sources. PS5 requires a different pathogenic variant at the same codon from a reputable non-ClinVar source.
PM1	Not met	Position 48 is located in the N-terminal region of BRIP1, outside the helicase domain (approximately residues 250–600). Cancerhotspots.org does not identify this residue as statistically significant. No literature evidence supports residue 48 as lying within a critical functional domain.
PM2	Met	NM_032043.3:c.143C>A is extremely rare in population databases: gnomAD v2.1 allele frequency is 0.00319% (1/31,388 alleles, genomes only, 0 homozygotes) and gnomAD v4.1 allele frequency is 0.00037% (6/1,613,830 alleles, 0 homozygotes) with grpmax filtering allele frequency of 1.24×10⁻⁶. Both are well below the 0.1% threshold for PM2 at supporting strength.	gnomad_v2 gnomad_v4
PM5	Not met	No same-residue pathogenic comparator variant was identified at codon 48. The PM5 candidate harvest did not find any alternate amino acid change at position 48 classified as pathogenic or likely pathogenic in ClinVar.	pm5_candidates
PM6	Not met	No de novo occurrence of NM_032043.3:c.143C>A has been reported. PM6 requires observation of the variant as de novo with unconfirmed maternity/paternity.
PP1	Not met	No family segregation data are available for NM_032043.3:c.143C>A. PP1 requires cosegregation of the variant with disease in multiple affected family members.
PP2	Not assessed	Insufficient data to assess whether BRIP1 has a low rate of benign missense variation. No missense constraint metric (e.g., Z-score, o/e ratio) is available in the evidence packet for this gene.
PP3	Met	In silico analysis supports a deleterious effect of NM_032043.3:c.143C>A (p.Thr48Lys). REVEL score is 0.728, above the 0.7 threshold for damaging prediction. Multiple clinical laboratories (GeneDx, Ambry Genetics, LabCorp) also cite in silico evidence for a deleterious effect in their ClinVar submissions. BayesDel score is 0.307, which is borderline; however, the weight of evidence from REVEL and the non-conservative nature of the Thr→Lys substitution supports a deleterious prediction at the supporting level.	revel bayesdel clinvar
PP4	Not met	No patient phenotype data or family history information is available for the individual(s) carrying NM_032043.3:c.143C>A. PP4 requires a phenotype or family history highly specific for BRIP1-related disease.
PP5	Not met	No reputable source reports NM_032043.3:c.143C>A as pathogenic. ClinVar classification is Uncertain significance with review status 'criteria provided, single submitter' (1-star). The ClinGen PP5/BP6 rule requires 3-star expert panel review to apply PP5 at supporting strength, which is not met here. No other reputable source classifies this variant as pathogenic.	clinvar
BA1	Not met	NM_032043.3:c.143C>A allele frequency is 0.00319% in gnomAD v2.1 and 0.00037% in gnomAD v4.1, both far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	NM_032043.3:c.143C>A allele frequency is 0.00319% in gnomAD v2.1 and 0.00037% in gnomAD v4.1, both far below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	NM_032043.3:c.143C>A has not been observed in the homozygous state in gnomAD (0 homozygotes across v2.1 and v4.1 combined) and has not been reported in trans with a known pathogenic BRIP1 variant.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established functional studies demonstrate that NM_032043.3:c.143C>A (p.Thr48Lys) has no deleterious effect on protein function or splicing.
BS4	Not met	No nonsegregation data are available for NM_032043.3:c.143C>A. BS4 requires lack of segregation with disease in affected family members.
BP1	Met	BRIP1 is a moderate-penetrance breast and ovarian cancer predisposition gene in which the predominant disease-causing mechanism is protein truncation. As established by Stratton and Rahman (2008, PMID:18163131), most disease-causing mutations in BRIP1 result in premature protein truncation or nonsense-mediated RNA decay, with only a small proportion likely to be rare missense variants disrupting critical functions. NM_032043.3:c.143C>A is a missense variant (p.Thr48Lys), and therefore BP1 applies at supporting benign strength.	PMID:18163131
BP2	Not met	NM_032043.3:c.143C>A has not been observed in trans with a known pathogenic BRIP1 variant. BRIP1-related cancer predisposition is autosomal dominant; observation in trans with a pathogenic variant would be required for BP2.
BP4	Not met	In silico analysis does not support a benign impact. REVEL score of 0.728 (>0.7 threshold) predicts a damaging effect on protein structure/function, contradicting BP4. SpliceAI shows no splice impact (max delta = 0.00), but the REVEL score indicates a deleterious missense change.	revel bayesdel spliceai
BP5	Not met	No alternate molecular basis for disease has been identified in an individual carrying NM_032043.3:c.143C>A. BP5 requires an alternative cause of the phenotype to be established.
BP6	Not met	No reputable source reports NM_032043.3:c.143C>A as benign. ClinVar classification is Uncertain significance with review status 'criteria provided, single submitter' (1-star). BP6 requires a reputable source to classify the variant as benign, which is not met.	clinvar
BP7	N/A	NM_032043.3:c.143C>A is a missense variant (p.Thr48Lys), not a synonymous or non-coding variant. BP7 applies only to synonymous variants without splice impact.
BP3	N/A	NM_032043.3:c.143C>A is a substitution variant, not an in-frame insertion/deletion. BP3 applies only to in-frame indels in repetitive regions without a known function.
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. BRIP1-related cancer predisposition is autosomal dominant; this criterion is not applicable.
PM4	N/A	NM_032043.3:c.143C>A is a missense substitution (p.Thr48Lys), not a protein length-altering variant (stop-loss, in-frame indel, or initiation codon change). PM4 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.