Variant classification summary

NM_007294.3:c.101C>T

BRCA1 · NP_009225.1:p.(Pro34Leu) · NM_007294.3

GRCh37: chr17:41267776 G>A · GRCh38: chr17:43115759 G>A

Gene: BRCA1 Transcript: NM_007294.3

Final call

PS3_Strong PP3_Supporting PP5_Supporting

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.(Pro34Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA1 c.101C>T (p.Pro34Leu) variant has not been observed in COSMIC and has been reported in ClinVar, where the ClinGen ENIGMA expert panel classified it as Likely Pathogenic.

2

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 (5/1,613,658 alleles; AF 3.10e-06; grpmax FAF 1.24e-06).

3

In a calibrated BRCA1 functional study summarized by the ENIGMA BRCA1 specification, c.101C>T (p.Pro34Leu) showed loss of function/complete functional impact, supporting PS3_Strong.

4

This missense change is located in the BRCA1 RING domain; BayesDel is 0.450189, above the ENIGMA PP3 threshold of 0.28, REVEL is 0.837, and SpliceAI predicts no significant splice impact with a max delta score of 0.01, supporting a damaging protein effect without predicted splice disruption.

Final determination: One strong and two supporting pathogenic criteria meet 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 missense variant does not fall into the BRCA1/ENIGMA PVS1 null-variant categories, and SpliceAI does not predict a splice effect (max delta score 0.01). Available evidence therefore does not support applying PVS1.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No validated evidence was identified showing that this variant produces the same amino acid or splice consequence as a different previously established pathogenic BRCA1 variant, so PS1 was not assessed.	cspec clinvar
PS2	N/A	De novo evidence is not used for BRCA1 in this ENIGMA framework, so PS2 is not applicable.	cspec
PS3	Met	In the ENIGMA BRCA1 functional evidence table, this exact variant is assigned PS3_Strong based on a calibrated functional study. The cited study reported loss-of-function/complete functional impact for c.101C>T (p.Pro34Leu), supporting a damaging effect on BRCA1 function.	cspec vcep_specifications_table9_v1_2_2024_11_18 PMID:30209399
PS4	Not assessed	No case-control study, odds ratio, or other quantitative enrichment data were identified showing that this variant is significantly more common in affected individuals than in controls, so PS4 was not assessed.	cspec clinvar
PM1	N/A	PM1 is designated not applicable in the ENIGMA BRCA1 specification and was not used for this variant.	cspec
PM2	Not met	This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 5/1,613,658 alleles (AF 3.10e-06; grpmax FAF 1.24e-06). The available control data therefore do not establish the ENIGMA requirement for absence from controls, so PM2 was not applied.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified for co-occurrence with another BRCA1 variant in a patient with BRCA1-related Fanconi anemia, so PM3 was not assessed.	cspec
PM4	N/A	PM4 is designated not applicable in the ENIGMA BRCA1 specification and was not used for this missense variant.	cspec
PM5	N/A	In the ENIGMA BRCA1 specification, PM5 is used here as a protein-truncating-code criterion for PTC variants with exon-specific weighting. This missense variant does not meet that variant-type requirement, so PM5 was not applied.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	PM6 is not used in this ENIGMA BRCA1 framework, so it is not applicable.	cspec
PP1	Not assessed	No segregation data were identified for this variant, and no quantitative co-segregation likelihood ratio was available, so PP1 was not assessed.	cspec clinvar
PP2	N/A	PP2 is not used in the ENIGMA BRCA1 specification and is not applicable.	cspec
PP3	Met	This missense variant lies in the BRCA1 RING domain, a clinically important functional domain, and BayesDel is 0.450189, which is above the ENIGMA PP3 threshold of 0.28. REVEL is also high at 0.837, while SpliceAI predicts no significant splice impact (max delta score 0.01), supporting a damaging protein effect rather than a splice-driven mechanism.	cspec bayesdel revel spliceai vcep_appendices_v1_2_2024_11_18
PP4	Not assessed	No variant-level personal or family history likelihood ratio meeting ENIGMA PP4 thresholds was identified for this 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	The highest available population filter allele frequency is far below the ENIGMA BA1 threshold of greater than 0.1%. In gnomAD v4.1, the grpmax FAF is 1.24e-06, so BA1 is not met.	cspec gnomad_v4
BS1	Not met	The available population frequency is below ENIGMA BS1 thresholds. The highest available grpmax FAF is 1.24e-06, which is below both the BS1_Supporting threshold of greater than 0.00002 and the BS1 threshold of greater than 0.0001.	cspec gnomad_v4
BS2	Not assessed	No data were identified showing the variant in individuals without features of BRCA1-related Fanconi anemia at a level that would satisfy the ENIGMA point-based BS2 framework, so BS2 was not assessed.	cspec
BS3	Not met	Available functional evidence does not show a benign or neutral effect. Instead, the ENIGMA BRCA1 functional evidence table assigns this exact variant PS3_Strong for damaging loss of function, so BS3 is not met.	cspec vcep_specifications_table9_v1_2_2024_11_18 PMID:30209399
BS4	Not assessed	No lack-of-segregation data or quantitative segregation likelihood ratio against pathogenicity was identified for this variant, so BS4 was not assessed.	cspec vcep_humu_40_1557_s001 vcep_pmid_17924331_easton_2007_ajhg
BP1	Not met	This missense variant is located in the BRCA1 RING domain (amino acids 2-101), which is a clinically important functional domain. The ENIGMA BP1_Strong rule applies only to missense or similar variants outside such domains with no predicted splice impact, so BP1 is not met.	cspec vcep_appendices_v1_2_2024_11_18 spliceai
BP2	N/A	BP2 is not used in the ENIGMA BRCA1 specification and is not applicable.	cspec
BP3	N/A	BP3 is not used in the ENIGMA BRCA1 specification and is not applicable.	cspec
BP4	Not met	This variant does not meet the ENIGMA BP4 rule because BayesDel is 0.450189, which is above the benign threshold of 0.15, although SpliceAI predicts no significant splice impact (max delta score 0.01). The computational evidence therefore does not support a benign interpretation.	cspec bayesdel spliceai
BP5	Not assessed	No variant-level multifactorial clinical likelihood ratio against pathogenicity was identified for this variant, so BP5 was not assessed.	cspec vcep_pmid_31853058_brca1_clinical_history_lr PMID:31853058
BP6	N/A	BP6 is not used in the ENIGMA BRCA1 specification and is not applicable.	cspec
BP7	N/A	This is a missense variant in the BRCA1 RING domain, not a silent or intronic variant, and no benign RNA assay evidence was identified. BP7 is therefore not applicable.	cspec spliceai

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