Variant classification summary

NM_007294.3:c.5561T>C

BRCA1 · NP_009225.1:p.(Leu1854Pro) · NM_007294.3

GRCh37: chr17:41197726 A>G · GRCh38: chr17:43045709 A>G

Gene: BRCA1 Transcript: NM_007294.3

Final call

Likely Pathogenic

PS3_Strong PP3_Supporting PP5_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.(Leu1854Pro)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.5561T>C (p.Leu1854Pro) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classifies it as likely pathogenic.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.

3

In calibrated BRCA1 functional studies summarized by ENIGMA, this variant showed damaging loss-of-function behavior consistent with pathogenic control variants in two studies, supporting PS3_Strong.

4

This missense change lies in the BRCA1 BRCT repeat domain; BayesDel no-AF is 0.406711, which is above the ENIGMA PP3 threshold of 0.28, REVEL is 0.731, and SpliceAI predicts no significant splice impact with a max delta score of 0.00, supporting a deleterious protein effect rather than a splicing effect.

Final determination: One Strong pathogenic criterion together with two Supporting pathogenic criteria meets the ENIGMA Table 3 rule for Likely Pathogenic.

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 is a missense variant, not a nonsense, frameshift, initiation-loss, or canonical ±1/2 splice variant, and SpliceAI predicts no splice effect (max delta score 0.00). Available evidence does not support applying PVS1 for this change.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not met	No previously classified pathogenic variant producing the same amino acid substitution was identified, so PS1 is not met.	cspec
PS2	N/A	This criterion is not applicable in the BRCA1 ENIGMA specification.	cspec
PS3	Met	In calibrated BRCA1 functional studies summarized by the ENIGMA expert panel, c.5561T>C (p.Leu1854Pro) showed damaging loss-of-function behavior similar to pathogenic control variants in two studies, supporting PS3_Strong.	vcep_specifications_table9_v1_2_2024_11_18 PMID:30209399 PMID:30765603
PS4	Not assessed	No case-control study or other quantitative evidence showing that this variant is significantly enriched in affected individuals versus controls was identified, so PS4 was not assessed.
PM1	N/A	Although this variant lies in the BRCA1 BRCT region, PM1 is not applicable in the BRCA1 ENIGMA specification, which handles domain information through other criteria.	cspec vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18
PM2	Not assessed	This variant is absent from gnomAD v2.1 and gnomAD v4.1, which supports rarity. However, ENIGMA PM2_Supporting requires absence in the specified population datasets with adequate coverage, and the full rule elements needed for formal PM2 assignment were not identified here, so PM2 was not assessed.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant occurred with another BRCA1 pathogenic variant in a patient with a phenotype consistent with BRCA1-related Fanconi anemia, so PM3 was not assessed.	cspec
PM4	N/A	This criterion is not applicable in the BRCA1 ENIGMA specification.	cspec
PM5	N/A	In the BRCA1 ENIGMA specification, PM5 is used for protein-termination variants in exons with prior proven pathogenic protein-termination variants. This variant is missense, so PM5 is not applicable.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This criterion is not applicable in the BRCA1 ENIGMA specification.	cspec
PP1	Not assessed	No quantitative segregation data were identified for this variant, so PP1 was not assessed.
PP2	N/A	This criterion is not applicable in the BRCA1 ENIGMA specification.	cspec
PP3	Met	This missense variant lies in the BRCA1 BRCT repeat domain, where ENIGMA allows PP3 for variants with predicted protein impact. BayesDel no-AF is 0.406711, which is above the ENIGMA PP3 threshold of 0.28, REVEL is 0.731, and SpliceAI shows no predicted splice effect (max delta score 0.00), supporting a deleterious protein effect and meeting PP3_Supporting.	cspec bayesdel revel spliceai vcep_appendices_v1_2_2024_11_18
PP4	Not assessed	No calibrated BRCA1 clinical-history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this exact variant, so PP4 was not assessed.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is not above the ENIGMA BA1 threshold of filter allele frequency greater than 0.1%. BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 and therefore is not above the ENIGMA BS1 thresholds of filter allele frequency greater than 0.002% or greater than 0.01%. BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified from unaffected individuals or from BRCA1-related recessive disease point scoring to support BS2, so this criterion was not assessed.	cspec
BS3	Not met	Available calibrated functional evidence does not show retained normal BRCA1 function for this variant. Instead, ENIGMA Table 9 summarizes damaging loss-of-function results in two studies, so BS3 is not met.	vcep_specifications_table9_v1_2_2024_11_18 PMID:30209399 PMID:30765603
BS4	Not assessed	No quantitative non-segregation data were identified for this variant, so BS4 was not assessed.
BP1	Not met	This missense variant is located in the BRCA1 BRCT functional domain rather than outside a clinically important domain, so the ENIGMA BP1_Strong rule is not met.	cspec vcep_appendices_v1_2_2024_11_18 spliceai
BP2	N/A	This criterion is not applicable in the BRCA1 ENIGMA specification.	cspec
BP3	N/A	This criterion is not applicable in the BRCA1 ENIGMA specification.	cspec
BP4	Not met	ENIGMA BP4 for missense variants in a clinically important domain requires BayesDel no-AF at or below 0.15 and SpliceAI at or below 0.1. Although SpliceAI is 0.00, BayesDel is 0.406711, which is above the benign threshold and instead supports PP3, so BP4 is not met.	cspec bayesdel spliceai vcep_appendices_v1_2_2024_11_18
BP5	Not assessed	No calibrated BRCA1 clinical-history likelihood ratio meeting ENIGMA BP5 thresholds was identified for this exact variant, so BP5 was not assessed.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	N/A	This criterion is not applicable in the BRCA1 ENIGMA specification.	cspec
BP7	N/A	This is a missense variant in the BRCA1 BRCT functional domain, and no RNA study showing a normal transcript effect was identified. The ENIGMA BP7 rules are not met for this variant.	cspec spliceai vcep_appendices_v1_2_2024_11_18

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