Variant classification summary

NM_007294.3:c.83T>C

BRCA1 · NP_009225.1:p.(Leu28Pro) · NM_007294.3

GRCh37: chr17:41267794 A>G · GRCh38: chr17:43115777 A>G

Gene: BRCA1 Transcript: NM_007294.3

Final call

Variant details

Gene

BRCA1

Transcript

NM_007294.3

Protein

NP_009225.1:p.(Leu28Pro)

gnomAD AF

ClinVar

Uncertain Significance

OncoKB

Inconclusive

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007294.3:c.83T>C (p.Leu28Pro) is a missense variant in BRCA1 exon 3, located within the RING domain (aa 2-101), a clinically important functional domain per ENIGMA specifications.

2

This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting ENIGMA PM2_Supporting.

3

In silico analysis predicts a deleterious effect: BayesDel no-AF score of 0.451556 exceeds the ENIGMA PP3 threshold of 0.28 for predicted damaging protein impact, and REVEL score is 0.832. SpliceAI predicts no splicing impact (max delta 0.00). These findings meet ENIGMA PP3 at Supporting strength.

4

BP4 is not met because the BayesDel score (0.451556) exceeds the ENIGMA benign prediction threshold of 0.15.

5

The variant is classified as Uncertain Significance (VUS) in ClinVar by the ENIGMA expert panel (ClinVar ID 55732), with 6 clinical laboratories reporting VUS and 1 reporting Likely Pathogenic.

6

Functional evidence (PS3/BS3) could not be assessed: ENIGMA Table 9 does not list c.83T>C, OncoKB classifies the effect as Inconclusive, and no publication abstract confirmed variant-specific functional data. The variant lies within the RING domain targeted by saturation genome editing studies (Findlay 2018, Starita 2015) but full-text verification is needed.

7

Clinical evidence (PP4/BP5 via Li et al. 2020 clinical history LR; PP1/BS4 via cosegregation) could not be assessed due to unavailability of variant-level data in the extracted materials.

Final determination:

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	PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, exon deletion) under ENIGMA BRCA1/2 v1.2.0. NM_007294.3:c.83T>C is a missense variant (p.Leu28Pro) and does not qualify.	cspec pvs1_variant_assessment
PS1	Not met	No previously classified pathogenic missense variant has been identified at BRCA1 codon 28. The ClinVar record for this variant (ID 55732) is classified as Uncertain Significance by the ENIGMA expert panel, and no publication abstract confirms the existence of a known pathogenic L28 substitution. PS1 requires a same-residue pathogenic comparator, which is absent.	clinvar pm5_candidates cspec
PS2	N/A	PS2 (de novo) is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0.	cspec
PS3	Not assessed	ENIGMA Table 9 (curated functional assay results) does not list c.83T>C. The functional assay supplementary dataset (ST4) excerpt did not include this variant. Key functional studies of the BRCA1 RING domain (Findlay 2018 PMID:30209399, Starita 2015 PMID:25823446, Clark 2022 PMID:35659930) do not mention c.83T>C or p.Leu28Pro in their abstracts. OncoKB classifies the functional effect as 'Inconclusive.' Full-text files are not available for verification. Without variant-specific functional evidence, PS3 cannot be assessed.	cspec oncokb
PS4	Not met	No case-control study demonstrating significantly increased prevalence in affected individuals (p≤0.05, OR≥4) has been identified for this variant. ENIGMA PS4 requires formal case-control comparison; available ClinVar and gnomAD data do not provide this.	cspec
PS5	N/A	PP5 (reputable source) is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0.	cspec
PM1	N/A	PM1 is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0. The criterion is superseded by ENIGMA's gene-specific bioinformatic code (PP3/BP4) and domain-aware PS1 rules.	cspec
PM2	Met	The variant is absent from gnomAD v2.1 (exome) and gnomAD v4.1, meeting the ENIGMA PM2_Supporting requirement: absent from controls in an outbred population in both gnomAD non-cancer subsets.	gnomad_v2 gnomad_v4 cspec
PM5	N/A	Under ENIGMA BRCA1/2 v1.2.0, PM5 is repurposed for PTC (protein termination codon) logic applicable to truncating variants in exons with established pathogenic PTCs. This is a missense variant; the PM5_PTC framework does not apply. Classic same-residue missense PM5 is also not applicable per the ENIGMA specification.	cspec pm5_candidates
PM6	N/A	PM6 (de novo) is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0.	cspec
PP1	Not assessed	No cosegregation data identified for this variant. No published family studies with quantitative cosegregation analysis found. ENIGMA PP1 requires co-segregation with disease in multiple affected family members with LR ≥2.08.	cspec
PP2	N/A	PP2 is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0.	cspec
PP3	Met	The variant is a missense substitution (p.Leu28Pro) located within the BRCA1 RING domain (aa 2-101), a clinically important functional domain per ENIGMA specifications. The BayesDel no-AF score is 0.451556, which exceeds the ENIGMA PP3 threshold of ≥0.28 for predicted deleterious protein impact. SpliceAI max delta is 0.00, consistent with a protein-change mechanism rather than splicing. REVEL score of 0.832 provides additional in silico support.	bayesdel revel spliceai cspec
PP4	Not assessed	ENIGMA PP4 requires multifactorial likelihood clinical data with LR ≥2.08 (Supporting). The Li et al. 2020 clinical history LR table (PMID:31853058) may contain data for c.83T>C, but the variant-level LR could not be verified from the extracted VCEP materials. No clinical history LR data is confirmed for this variant.	cspec
PP5	N/A	PP5 (reputable source) is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0.	cspec
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1. ENIGMA BA1 requires a filter allele frequency >0.001 (0.1%) in gnomAD non-cancer, non-founder populations. Absence does not meet this threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1. ENIGMA BS1_Supporting requires FAF >0.00002 and BS1_Strong requires FAF >0.0001. Absence does not meet either threshold.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	ENIGMA BS2 requires observation in healthy adults without Fanconi Anemia features. No such data is available for this variant.	cspec
BS3	Not assessed	ENIGMA Table 9 does not list a pre-assigned BS3 code for c.83T>C. OncoKB classifies the biological effect as 'Inconclusive.' No variant-specific functional evidence demonstrating no damaging effect on protein function was confirmed in available publication abstracts. Full-text verification of functional assay data (Findlay 2018, Starita 2015, Clark 2022) is needed.	cspec oncokb
BS4	Not assessed	No segregation data demonstrating lack of cosegregation in affected family members has been identified for this variant. ENIGMA BS4 requires quantitative cosegregation analysis with LR ≤0.48 (Supporting).	cspec
BP1	N/A	ENIGMA BP1 applies to missense variants located OUTSIDE a clinically important functional domain with no splicing predicted (SpliceAI ≤0.1). This variant is at position 28, which is INSIDE the RING domain (aa 2-101), a clinically important functional domain. BP1 therefore does not apply.	cspec spliceai
BP2	N/A	BP2 is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0.	cspec
BP3	N/A	BP3 is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0 (in-frame indels only; not relevant for substitution variants).	cspec
BP4	Not met	ENIGMA BP4 for missense variants inside a clinically important functional domain requires BayesDel no-AF ≤0.15 AND SpliceAI ≤0.1. The BayesDel no-AF score for this variant is 0.451556, which exceeds the 0.15 threshold for benign prediction. Therefore BP4 is not met.	bayesdel spliceai cspec
BP5	Not assessed	ENIGMA BP5 requires multifactorial likelihood clinical data supporting benignity (LR ≤0.48 for Supporting). The Li et al. 2020 clinical history LR table (PMID:31853058) may contain data for c.83T>C, but the variant-level LR could not be verified. No clinical history LR data is confirmed for this variant.	cspec
BP6	N/A	BP6 (reputable source) is not applicable under ENIGMA BRCA1/2 CSPEC v1.2.0.	cspec
BP7	N/A	ENIGMA BP7_Supporting applies to silent variants inside functional domains (if BP4 met) or intronic variants outside conserved splice motifs (if BP4 met). This is a missense variant and does not qualify for either BP7_Supporting path. ENIGMA BP7_Strong(RNA) applies to missense variants outside functional domains with mRNA assay evidence; this variant is inside the RING domain and lacks confirmed mRNA assay data. BP7 is therefore not applicable.	cspec spliceai

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