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NM_007294.4:c.598G>A
p.Gly200Arg · BRCA1
ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.2 · v1.2
0%
complete
Final classification
VUS
BP1
BRCA1
c.598G>A
p.Gly200Arg
missense · exon 9
Gene context NCBI Gene ↗ OncoKB ↗

BRCA1 encodes a large nuclear protein that helps maintain genomic stability by coordinating the repair of DNA double-strand breaks through homologous recombination, and it also regulates transcription and the cell cycle. It acts as a tumor suppressor, working with proteins such as RAD51, BRCA2, BARD1, and PALB2 to preserve genome integrity. Inherited alterations in BRCA1 cause hereditary breast and ovarian cancer syndrome, with elevated risks of breast, ovarian, prostate, and pancreatic cancers, and biallelic loss underlies a rare form of Fanconi anemia. Because BRCA1-driven tumors rely on impaired DNA repair, they are treatable with PARP inhibitors.

This variant

This BRCA1 missense variant affects a tumor-suppressor protein involved in homologous-recombination repair and maintenance of genomic stability.

Transcript
NM_007294.4
HGVS · transcript:coding
NM_007294.4:c.598G>A
GRCh38
chr17:43095918 C>T
GRCh37
chr17:41247935 C>T
VUS: BP1 (strong) is the only met criterion, and ENIGMA Table 3 provides no qualifying pathogenic or benign combination from it alone.
Classification rationale
BP1 VUS
BRCA1 c.598G>A missense · exon 9

VUS: BP1 (strong) applies because Gly200 lies outside the approved BRCA1 domains and SpliceAI is 0.019.

BP1 → VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
Gene diagram · NM_007294.4 · variants mapped to exon structure
BRCA1 NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength Supporting Moderate Strong Very strong
BP1 strong Benign
Met, strong: Gly200 is outside approved BRCA1 domains and SpliceAI max delta 0.019 is below the VCEP <=0.1 no-splicing threshold.
ENIGMA BRCA1 v1.2 specifies BP1_Strong for silent, missense, or in-frame insertion/deletion variants outside a potentially clinically important functional domain with no predicted splicing (SpliceAI <=0.1).The VCEP-defined BRCA1 domains are RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; residue 200 is outside all three.SpliceAI reports a maximum delta score of 0.019 for NM_007294.4:c.598G>A, satisfying the VCEP no-predicted-splicing condition.
cspec ↗spliceai ↗
Assessed · not applied · 2 not met · 13 not assessed
Pathogenic
PS1 Not assessed: no pathogenic or likely pathogenic comparator producing p.Gly200Arg was identified, although SpliceAI 0.019 meets the VCEP no-splicing condition of <=0.1.
PS3 Not assessed: no variant-specific calibrated protein-function assay result was found for c.598G>A/p.Gly200Arg in the governing ENIGMA sources.
PS4 Not assessed: no case-control odds ratio, p-value, or confidence interval is available to compare with the ENIGMA PS4 thresholds (OR >=4; p <=0.05; lower CI >2.0).
PM2 Not assessed: variant is absent from both specified non-cancer gnomAD datasets, but the required regional average read depth of at least 25 is not reported.
PM3 Not assessed: no qualifying Fanconi anemia proband, pathogenic BRCA1 allele in trans, phase information, or Table 6 PM3 points are documented.
PP1 Not assessed: no affected-family segregation or quantitative LR is available, so the ENIGMA PP1 thresholds cannot be applied.
PP3 Not met: missense REVEL score 0.599 is below the supporting PP3 threshold of >=0.644.
PP4 Not assessed: no combined clinical likelihood ratio is available to compare with the ENIGMA PP4 supporting threshold (LR >=2.08).
Benign
BA1 Not assessed: reported maximum observed AF is 1.6021e-05, below the 0.001 BA1 threshold, but governing FAF and read-depth values are unavailable.
BS1 Not assessed: highest observed AF is 1.6021e-05, below the 0.00002 BS1 Supporting threshold, but governing FAF and read-depth values are unavailable.
BS2 Not assessed: gnomAD reports 0 homozygotes, but the VCEP excludes frequency data from BS2 and provides no qualifying clinical-cohort observations or age data.
BS3 Not assessed: no variant-specific calibrated benign protein-function assay result was found for c.598G>A/p.Gly200Arg in the governing ENIGMA sources.
BS4 Not assessed: no affected-family non-segregation or quantitative LR is available, so the ENIGMA BS4 thresholds cannot be applied.
BP4 Not met: missense REVEL score 0.599 exceeds the supporting BP4 threshold of <=0.29 and is gray-zone.
BP5 Not assessed: no combined clinical likelihood ratio is available to compare with the ENIGMA BP5 supporting threshold (LR <=0.48).
N/A · 12 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.24086e-06; MAF= 0.00012%, 2/1611782 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6021e-05; MAF= 0.00160%, 1/62418 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012% · 2 / 1,611,782
0 hom
Remaining individuals
1 / 62,418
0.0016%
European (non-Finnish)
1 / 1,178,212
8.5e-05%
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.599. BayesDel score = 0.0537567.
SpliceAI ↗
Functional / OncoKB screenshot
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. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58798374, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots