Variant classification summary

NM_007294.4:c.4327C>G

BRCA1 · NP_009225.1:p.(Arg1443Gly) · NM_007294.4

GRCh37: chr17:41234451 G>C · GRCh38: chr17:43082434 G>C

Gene: BRCA1 Transcript: NM_007294.4

Final call

Benign

BS3_Strong BP1_Strong BS1_Supporting BP6_Supporting_Benign

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Arg1443Gly)

gnomAD AF

ClinVar

OncoKB

Likely Neutral

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.4327C>G (p.Arg1443Gly; p.R1443G) variant has been reported in ClinVar, where the aggregate classification is Benign with expert panel review.

2

This variant is present in population databases, including gnomAD v2.1 at 9/282760 alleles (AF 3.18291e-05; grpmax FAF 2.294e-05) and gnomAD v4.1 at 65/1613954 alleles (AF 4.02738e-05; grpmax FAF 3.666e-05), which exceeds the BRCA1 BS1 supporting threshold of 0.00002 but remains below the BA1 threshold of 0.001.

3

In two calibrated functional studies curated by ENIGMA, this variant showed no functional impact and protein behavior similar to benign control variants, supporting BS3 at strong strength.

4

Computational evidence does not support a damaging effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, BayesDel no-AF is -0.285466, and REVEL is 0.007; because Arg1443 lies outside the BRCA1 ENIGMA clinically important functional domains, this profile supports BP1_Strong rather than PP3.

Final determination: Under ENIGMA BRCA1/BRCA2 Specification v1.2 Table 3, two strong benign criteria, BS3_Strong and BP1_Strong, support a Benign classification.

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	This missense substitution does not fall into the BRCA1 PVS1 null-variant categories, and SpliceAI predicts no significant splice effect (max delta score 0.01), so PVS1 is not applicable on the reviewed evidence.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No reviewed evidence established a previously classified pathogenic or likely pathogenic variant with the same amino acid change or the same proven splice effect, so PS1 was not assessed.	cspec clinvar
PS2	N/A	PS2 is not applicable in the BRCA1 ENIGMA specification.	cspec
PS3	Not met	Available functional evidence does not support a damaging effect. In the ENIGMA BRCA1 functional dataset, this variant showed no functional impact and was curated as meeting BS3 rather than PS3.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PS4	Not assessed	No case-control study or other reviewed dataset showed a significant enrichment of this variant in affected individuals compared with controls, so PS4 was not assessed.	cspec clinvar
PM1	N/A	PM1 is not applicable in the BRCA1 ENIGMA specification.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at 9/282760 alleles (AF 3.18291e-05) and in gnomAD v4.1 at 65/1613954 alleles (AF 4.02738e-05), so the BRCA1 PM2 absence-from-controls rule is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No reviewed evidence showed this variant in a patient with BRCA1-related Fanconi anemia and an informative co-occurring BRCA1 variant, so PM3 was not assessed.	cspec
PM4	N/A	PM4 is not applicable in the BRCA1 ENIGMA specification.	cspec
PM5	N/A	In the BRCA1 ENIGMA specification, PM5 is used for protein-truncating variants in eligible exons rather than for this missense substitution, so PM5 is not applicable.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	PM6 is not applicable in the BRCA1 ENIGMA specification.	cspec
PP1	Not assessed	No segregation analysis with a quantitative likelihood ratio was identified for this variant, so PP1 was not assessed.	cspec clinvar
PP2	N/A	PP2 is not applicable in the BRCA1 ENIGMA specification.	cspec
PP3	Not met	Computational evidence does not support a damaging effect. BayesDel no-AF is -0.285466, below the BRCA1 PP3 threshold of 0.28, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, below the PP3 splice threshold of 0.2. REVEL is also low at 0.007.	cspec spliceai bayesdel revel
PP4	Not assessed	No variant-specific clinical-history likelihood ratio meeting the BRCA1 ENIGMA PP4 thresholds was identified in the reviewed materials, so PP4 was not assessed.	cspec vcep_pmid_31853058_brca1_clinical_history_lr vcep_pmid_31853058_li_2020_geneticsinmedicine
PP5	N/A	PP5 is not applicable in the BRCA1 ENIGMA specification.	cspec
BA1	Not met	The filter allele frequency does not reach the BRCA1 BA1 threshold of greater than 0.001. The observed grpmax FAF is 2.294e-05 in gnomAD v2.1 and 3.666e-05 in gnomAD v4.1, both well below that threshold.	cspec gnomad_v2 gnomad_v4
BS1	Met	The population frequency exceeds the BRCA1 BS1 supporting threshold of greater than 0.00002 but does not exceed the strong threshold of greater than 0.0001. The grpmax FAF is 2.294e-05 in gnomAD v2.1 and 3.666e-05 in gnomAD v4.1, supporting BS1 at supporting strength.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No reviewed proband data were available to assign BS2 points based on absence of Fanconi anemia features, so BS2 was not assessed.	cspec
BS3	Met	In two calibrated functional studies curated by ENIGMA, this variant showed protein function similar to benign control variants and no functional impact, supporting BS3 at strong strength.	vcep_specifications_table9_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
BS4	Not assessed	No quantitative non-segregation study or other reviewed pedigree evidence arguing against disease segregation was identified, so BS4 was not assessed.	cspec vcep_humu_40_1557_s001 vcep_pmid_17924331_easton_2007_ajhg
BP1	Met	This missense variant lies outside the BRCA1 clinically important functional domains defined by ENIGMA, and no splice effect is predicted. Arg1443 is outside the RING domain (aa 2-101), the coiled-coil domain (aa 1391-1424), and the BRCT repeats (aa 1650-1857), and SpliceAI shows a max delta score of 0.01, supporting BP1 at strong strength. REVEL is also low at 0.007.	cspec vcep_appendices_v1_2_2024_11_18 spliceai revel
BP2	N/A	BP2 is not applicable in the BRCA1 ENIGMA specification.	cspec
BP3	N/A	BP3 is not applicable in the BRCA1 ENIGMA specification.	cspec
BP4	Not met	Available computational evidence is benign-leaning, but the BRCA1 BP4 rule is restricted to missense variants inside a clinically important functional domain with BayesDel no-AF 0.15 or lower and SpliceAI 0.1 or lower. This variant is outside those domains, so BP4 is not applied here. BayesDel is -0.285466, SpliceAI max delta score is 0.01, and REVEL is 0.007; this benign computational profile is captured by BP1_Strong rather than BP4.	cspec vcep_appendices_v1_2_2024_11_18 bayesdel spliceai revel
BP5	Not assessed	No variant-specific clinical-history likelihood ratio meeting the BRCA1 ENIGMA BP5 thresholds was identified in the reviewed clinical-history materials, so BP5 was not assessed.	cspec vcep_pmid_31853058_brca1_clinical_history_lr vcep_pmid_31853058_li_2020_geneticsinmedicine
BP6	Met	Expert panel Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) classified as Benign.	cspec clinvar
BP7	Not assessed	No reviewed RNA study showed a normal transcript profile for this variant, so BP7 was not assessed.	cspec spliceai

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.