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.1 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.2 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).3
BRIP1
Final classification
VUS
BRIP1 c.611C>G · p.Ser204Cys
BRIP1
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
BRIP1 c.611C>G
PM2 + BP4
→
VUS
Gene diagram
· NM_032043.3 · variants mapped to exon structure
BRIP1
NM_032043.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
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 v2.1: absent (AF=null)gnomAD v4.1: absent (AF=null)gnomAD-Canada v1.0: absent (AC=0
✓
BP4
supporting
Benign
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: 0.24BayesDel: -0.212SpliceAI max delta: 0.00 — all three in silico tools predict a benign effect.
Assessed · not applied
Pathogenic
PS1
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
No reports of de novo occurrence of this variant (with confirmed maternity and paternity) were identified in the literature or databases.
PS3
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
No case-control studies demonstrate a statistically significant enrichment of this variant in affected individuals compared to population controls.
PM1
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.
PM5
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
No reports of a de novo occurrence of this variant without confirmation of parental identity were identified.
PP1
No co-segregation data with disease in families harboring this variant have been published; no LOD scores or pedigree analyses are available.
PP2
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
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).
PP4
No patient phenotype or family history information is available for this case to assess specificity of clinical presentation.
PP5
No reputable source (e.g., clinical diagnostic laboratory, expert panel) recently reports this variant as pathogenic without supporting evidence available for independent evaluation.
Benign
BA1
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%.
BS1
This variant is absent from all population databases; allele frequency of 0 does not exceed the BS1 threshold of >0.3%.
BS2
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
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
No segregation data demonstrating lack of co-segregation with disease in affected families are available.
BP1
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
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.
BP5
No clinical case information is available demonstrating an alternate molecular basis for disease in a proband harboring this variant.
BP6
No reputable source (e.g., clinical diagnostic laboratory, expert panel) recently reports this variant as benign without supporting evidence available for independent evaluation.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.24. BayesDel score = -0.212169.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRIP1, a DEAH helicase, is altered by mutation and amplification in various cancers, including breast cancer and melanoma.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links