Variant classification summary

NM_007294.4:c.305C>G

BRCA1 · NP_009225.1:p.(Ala102Gly) · NM_007294.4

GRCh37: chr17:41256275 G>C · GRCh38: chr17:43104258 G>C

Gene: BRCA1 Transcript: NM_007294.4

Final call

Benign

BS3_Strong BP1_Strong BP6_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.4

Protein

NP_009225.1:p.(Ala102Gly)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.305C>G (p.Ala102Gly) variant has been reported in ClinVar and includes a Benign expert-panel classification from the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 at AF 2.49e-06 (4/1609246 alleles), with a highest observed subpopulation AF of 4.81e-05 (3/62354 alleles).

3

A calibrated BRCA1 functional assay reported no damaging effect for p.Ala102Gly, and ENIGMA assigns BS3_Strong for this variant.

4

SpliceAI predicts no significant splice impact with a max delta score of 0.01, and the ENIGMA BRCA1 bioinformatic dataset reports BayesDel 0.14; together with the variant's position outside the BRCA1 RING domain (aa 2-101), this supports a benign missense interpretation.

Final determination: Benign based on two strong benign criteria under the ENIGMA BRCA1/BRCA2 Table 3 combining rules (BS3_Strong and BP1_Strong); BP6_Supporting is concordant additional benign evidence.

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	This missense variant does not create a nonsense, frameshift, canonical +/-1,2 splice, initiation-codon, or exon-level loss-of-function event, so the BRCA1 PVS1 rule is not met.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No evidence was identified showing that this variant causes the same protein or splicing consequence as a previously classified pathogenic or likely pathogenic BRCA1 variant, so PS1 was not assessed.	cspec
PS2	N/A	De novo evidence is not part of the ENIGMA BRCA1/2 framework for this gene, so PS2 is not applicable.	cspec
PS3	Not met	Available functional evidence does not support a damaging effect. A calibrated BRCA1 functional study reported no functional impact for p.(Ala102Gly), so PS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18 PMID:30219179
PS4	Not assessed	No case-control study or other quantitative prevalence data were identified showing that this variant is significantly enriched in affected individuals compared with controls, so PS4 was not assessed.	cspec clinvar
PM1	N/A	PM1 is not applicable in the ENIGMA BRCA1/2 framework.	cspec
PM2	Not met	This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at AF 2.49e-06 (4/1609246 alleles; highest subpopulation AF 4.81e-05, 3/62354), so it is not absent from population databases and PM2 is not applied.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified for biallelic BRCA1 variation in a proband with BRCA1-related Fanconi anemia, so PM3 was not assessed.	cspec
PM4	N/A	PM4 is not applicable in the ENIGMA BRCA1/2 framework.	cspec
PM5	Not assessed	The ENIGMA BRCA1/2 PM5 rule is mainly used for protein-truncating variants in eligible exons, and no qualifying codon-level pathogenic comparator was identified for this missense variant, so PM5 was not assessed.	cspec vcep_specifications_table4_v1_2_2024_11_18 vcep_supplementarytables_v1_2_2024_11_18
PM6	N/A	PM6 is not applicable in the ENIGMA BRCA1/2 framework.	cspec
PP1	Not assessed	No quantitative co-segregation data were identified for affected relatives, so PP1 was not assessed.	cspec
PP2	N/A	PP2 is not applicable in the ENIGMA BRCA1/2 framework.	cspec
PP3	Not met	Available predictive evidence does not meet the ENIGMA BRCA1/2 thresholds for PP3. SpliceAI predicts no significant splice effect with a max delta score of 0.01, which is below the 0.2 threshold, and the ENIGMA bioinformatic dataset reports BayesDel 0.14, which is below the 0.28 threshold for pathogenic computational support.	cspec spliceai vcep_supplementarytables_v1_2_2024_11_18
PP4	Not met	The BRCA1 clinical-history likelihood ratio for this variant is 0.688 in 2 probands, which is below the ENIGMA PP4 supporting threshold of 2.08, so PP4 is not met.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	N/A	PP5 is not applicable in the ENIGMA BRCA1/2 framework.	cspec
BA1	Not met	This variant does not meet BA1 because it is absent from gnomAD v2.1 and its observed gnomAD v4.1 frequency is 2.49e-06, which is far below the ENIGMA BA1 threshold of 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant does not meet BS1 because it is absent from gnomAD v2.1 and its highest observed gnomAD v4.1 subpopulation frequency is 4.81e-05, which is above the BS1 supporting threshold of 2e-05 but below the BS1 strong threshold of 1e-04; however the ENIGMA BS1 rule is defined using filter allele frequency in gnomAD v2.1 and/or v3.1, and no qualifying FAF evidence was identified.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No data were identified showing this variant in individuals evaluated for absence of BRCA1-related Fanconi anemia features under the ENIGMA point-based BS2 framework, so BS2 was not assessed.	cspec
BS3	Met	A calibrated BRCA1 functional study found no damaging effect for p.(Ala102Gly). ENIGMA Table 9 assigns BS3_Strong based on one calibrated study showing protein function similar to benign control variants (PMID:30219179).	cspec vcep_specifications_table9_v1_2_2024_11_18 PMID:30219179
BS4	Not assessed	No quantitative evidence for lack of segregation in affected relatives was identified, so BS4 was not assessed.	cspec
BP1	Met	This is a missense variant located just outside the BRCA1 clinically important RING domain, which is defined as amino acids 2-101, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is below the 0.1 threshold. This meets ENIGMA BP1_Strong for a missense variant outside a clinically important domain without predicted splice disruption.	cspec spliceai vcep_appendices_v1_2_2024_11_18 vcep_specifications_v1_2_2024_11_18
BP2	N/A	BP2 is not applicable in the ENIGMA BRCA1/2 framework.	cspec
BP3	N/A	BP3 is not applicable in the ENIGMA BRCA1/2 framework.	cspec
BP4	N/A	For BRCA1 missense variants, BP4 applies within a clinically important functional domain when BayesDel is 0.15 or less and SpliceAI is 0.1 or less. This variant is outside the BRCA1 clinically important domains, so BP4 is not the applicable benign bioinformatic rule.	cspec spliceai vcep_appendices_v1_2_2024_11_18
BP5	Not met	The BRCA1 clinical-history likelihood ratio for this variant is 0.688 in 2 probands, which is above the ENIGMA BP5 supporting threshold of 0.48, so BP5 is not met.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP7	Not assessed	No variant-specific mRNA assay showing a normal transcript profile was identified, 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.