NM_032043.3:c.611C>G

BRIP1 · NP_114432.2:p.(Ser204Cys) · NM_032043.3

GRCh37: chr17:59924478 G>C · GRCh38: chr17:61847117 G>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.(Ser204Cys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_032043.3:c.611C>G (p.Ser204Cys) is a missense variant in BRIP1 that is absent from all large population databases including gnomAD v2.1, v4.1, and gnomAD-Canada.

Multiple in silico predictors (REVEL 0.24, BayesDel -0.212, SpliceAI max delta 0.00) indicate this variant is tolerated and does not affect splicing.

No variant-specific functional studies, case-control data, co-segregation data, or de novo observations were identified for this variant in the peer-reviewed literature.

Applying generic ACMG/AMP 2015 classification rules (PMID:25741868): one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) are met, resulting in insufficient evidence for classification; the variant is a Variant of Uncertain Significance (VUS).

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.611C>G is a missense variant (p.Ser204Cys) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants; PVS1 is not applicable.	pvs1_generic_framework
PS1	Not assessed	No alternate nucleotide change at codon 204 leading to the same p.Ser204Cys missense change has been identified in ClinVar or the literature as pathogenic; PS1 cannot be assessed.
PS2	Not assessed	No reports of de novo occurrence of this variant (with confirmed maternity and paternity) were identified in the literature or databases.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrating a damaging effect of p.Ser204Cys on BRIP1 protein function have been identified in the peer-reviewed literature.
PS4	Not met	No case-control studies demonstrate a statistically significant enrichment of this variant in affected individuals compared to population controls.
PS5	N/A	PS5 is not a criterion in the standard ACMG/AMP 2015 framework (PMID:25741868); no BRIP1-specific VCEP defines an extended PS5 rule.
PM1	Not met	Residue 204 lies within the DEAD-like helicase domain (residues ~1-440) but is not located within a defined mutational hotspot or a critical functional domain with established clustering of pathogenic missense variants.
PM2	Met	This variant is absent from all large population databases including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with an allele frequency well below the 0.1% threshold for PM2.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not assessed	No pathogenic missense variants at codon 204 involving a different amino acid change were identified in ClinVar; PM5 cannot be assessed without a same-residue comparator.
PM6	Not met	No reports of a de novo occurrence of this variant without confirmation of parental identity were identified.
PP1	Not met	No co-segregation data with disease in families harboring this variant have been published; no LOD scores or pedigree analyses are available.
PP2	Not met	Insufficient evidence that BRIP1 has a low rate of benign missense variation and that missense variants are a common mechanism of disease; many BRIP1 missense variants remain classified as VUS.
PP3	Not met	Multiple in silico predictors do not support a deleterious effect: REVEL score 0.24 (below 0.5 damaging threshold), BayesDel score -0.212 (benign-polar), and SpliceAI max delta 0.00 (no splicing impact predicted).	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history information is available for this case to assess specificity of clinical presentation.
PP5	Not met	No reputable source (e.g., clinical diagnostic laboratory, expert panel) recently reports this variant as pathogenic without supporting evidence available for independent evaluation.
BA1	Not met	This variant is absent from all large population databases (gnomAD v2.1, v4.1, gnomAD-Canada); allele frequency of 0 does not exceed the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from all population databases; allele frequency of 0 does not exceed the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No evidence that this variant has been observed in homozygous state, in trans with a pathogenic variant, or in healthy adult individuals with full penetrance expected at an early age.
BS3	Not assessed	A 2024 bioRxiv preprint (Putnam et al.) from exploratory search suggests p.Ser204Cys has near-wildtype function in a multiplexed assay of variant effect; however, these data are not peer-reviewed and a single preprint does not constitute well-established functional evidence sufficient to meet BS3.
BS4	Not assessed	No segregation data demonstrating lack of co-segregation with disease in affected families are available.
BP1	Not met	Although BRIP1 loss-of-function is an established disease mechanism, pathogenic missense variants have been reported in BRIP1; insufficient evidence exists to conclude that primarily truncating variants are known to cause BRIP1-related disease to the exclusion of missense variants.
BP2	Not assessed	This variant has not been observed in trans with a known pathogenic BRIP1 variant in an individual with a fully penetrant dominant disorder, nor in cis with a pathogenic BRIP1 variant.
PM3	N/A	Skipped per instructions: PM3 applies to recessive disorders with in trans observation; BRIP1 germline context is dominant cancer predisposition and no in trans data exist.
PM4	N/A	Skipped per instructions: PM4 applies to in-frame deletions/insertions or stop-loss variants; this is a missense substitution.
BP3	N/A	Skipped per instructions: BP3 applies to in-frame deletions/insertions in repeating regions; this is a missense substitution.
BP4	Met	Multiple lines of computational evidence suggest no impact on gene product: REVEL score 0.24 (below pathogenic threshold), BayesDel score -0.212 (benign-polar), and SpliceAI max delta 0.00 (no predicted splicing alteration).	revel bayesdel spliceai
BP5	Not assessed	No clinical case information is available demonstrating an alternate molecular basis for disease in a proband harboring this variant.
BP6	Not met	No reputable source (e.g., clinical diagnostic laboratory, expert panel) recently reports this variant as benign without supporting evidence available for independent evaluation.
BP7	N/A	BP7 applies to synonymous (silent) variants; NM_032043.3:c.611C>G is a missense variant (p.Ser204Cys).

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