Variant classification summary

NM_000059.3:c.5218_5223del

BRCA2 · NP_000050.2:p.(Leu1740_Ser1741del) · NM_000059.3

GRCh37: chr13:32913708 ATTTAAG>A · GRCh38: chr13:32339571 ATTTAAG>A

Gene: BRCA2 Transcript: NM_000059.3

Final call

Benign

BS1 strong benign BP1 strong benign

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Leu1740_Ser1741del)

gnomAD AF

6.213742810699568e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000059.3:c.5218_5223del (p.Leu1740_Ser1741del) is an in-frame deletion of 6 nucleotides in BRCA2 exon 11, removing two amino acids (Leu1740 and Ser1741) from a region between BRC repeats 5 and 6, outside the ENIGMA-defined clinically important functional domains.

2

The variant is present in gnomAD population databases at a grpmax filter allele frequency of 0.0106% (FAF = 0.000106) in gnomAD v2.1 exomes, exceeding the ENIGMA BS1 Strong threshold of > 0.01% (FAF > 0.0001). Highest subpopulation frequency is in East Asians (AF = 0.030%, 6/19,916 alleles). No homozygotes observed.

3

As an in-frame deletion located outside the ENIGMA-defined clinically important functional domains (PALB2 binding aa 10–40; DNA binding aa 2481–3186) with no splicing impact predicted (SpliceAI max delta = 0.00), ENIGMA BP1_Strong is met: in-frame deletion outside a clinically important domain without splicing prediction.

4

Clinical-history likelihood ratio from Li et al. 2020 (PMID:31853058) is 0.77 (8 probands), falling in the neutral zone. Neither PP4 nor BP5 is applicable.

5

This variant has been reported in ClinVar as Uncertain significance by 9 clinical laboratories and Likely benign by 1 clinical laboratory (ClinVar Variation ID: 51824; review status: criteria provided, single submitter). No expert panel classification exists.

6

No functional studies, case-control data, segregation data, or variant-specific publications were identified for this variant. Five publications were reviewed in full text; none mention NM_000059.3:c.5218_5223del.

7

Applying the ENIGMA Table 3 combining rules: two Strong Benign criteria (BS1 + BP1) satisfy the Benign classification threshold (Strong Benign ≥ 2). This variant is classified as BENIGN.

Final determination: ENIGMA Table 3 Benign rule: 2 or more Strong Benign criteria (BS1_Strong + BP1_Strong) classify the variant as Benign.

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	NM_000059.3:c.5218_5223del is an in-frame deletion (p.Leu1740_Ser1741del) removing 6 nucleotides in exon 11. It is not a null variant (nonsense, frameshift, or canonical ±1,2 splice site) and therefore does not meet the ENIGMA BRCA2 PVS1 entry criteria as defined in Specifications Table 4.	cspec pvs1_variant_assessment pvs1_gene_context vcep_specifications_table4_v1_2_2024_11_18
PS1	N/A	PS1 requires a missense substitution comparator or a variant with the same predicted splicing impact as a known pathogenic variant. This is an in-frame deletion, not a missense change, and SpliceAI predicts no splicing impact (max delta = 0.00). No applicable comparator exists.	cspec spliceai
PS2	N/A	ENIGMA BRCA2 specification marks PS2 as Not Applicable.
PS3	Not met	No variant-specific or systematic-range functional data identified for NM_000059.3:c.5218_5223del. ENIGMA Table 9 (curated functional assays) covers only missense and synonymous BRCA2 variants; this in-frame deletion is not listed. Literature review of 5 publications identified no functional studies of this variant.	vcep_specifications_table9_v1_2_2024_11_18 cspec
PS4	Not met	No case-control study demonstrating significantly increased prevalence of this variant in affected individuals versus controls has been identified. ENIGMA PS4 requires p ≤ 0.05 and OR ≥ 4. No such data available for this variant.	cspec
PS5	N/A	PS5 is not defined in the ENIGMA BRCA2 specification (version 1.2). No gene-specific rules exist for this criterion.
PM1	N/A	ENIGMA BRCA2 specification marks PM1 as Not Applicable.
PM2	Not met	ENIGMA PM2 (Supporting) requires absence from gnomAD controls. This variant is present in gnomAD v2.1 (7/280,116 alleles, AF = 2.50 × 10⁻⁵) and gnomAD v4.1 (10/1,609,336 alleles, AF = 6.21 × 10⁻⁶), with highest subpopulation frequency in East Asian (AF = 0.030% in v2.1). The variant is not absent from outbred population controls.	gnomad_v2 gnomad_v4 cspec
PM4	N/A	ENIGMA BRCA2 specification marks PM4 as Not Applicable.
PM5	N/A	ENIGMA repurposes PM5 for PTC (premature termination codon) variants only (PM5_PTC). This variant is an in-frame deletion, not a PTC. Classic same-residue missense PM5 does not apply to in-frame deletions.	cspec vcep_specifications_table4_v1_2_2024_11_18 pm5_candidates
PM6	N/A	ENIGMA BRCA2 specification marks PM6 as Not Applicable.
PP1	Not met	No co-segregation data available for this variant. ENIGMA PP1 requires quantitative co-segregation analysis with LR ≥ 2.08 for Supporting strength.	cspec
PP2	N/A	ENIGMA BRCA2 specification marks PP2 as Not Applicable.
PP3	Not met	This in-frame deletion (p.Leu1740_Ser1741del) lies outside the two ENIGMA-defined clinically important functional domains (BRCA2 PALB2 binding domain aa 10–40; BRCA2 DNA binding domain aa 2481–3186). SpliceAI predicts no splicing impact (max delta = 0.00). PP3 requires either location inside a clinically important domain with BayesDel ≥ 0.30, or SpliceAI ≥ 0.2. Neither condition is met.	cspec spliceai
PP4	Not met	Clinical-history likelihood ratio (LR) from Li et al. 2020 (PMID:31853058) for NM_000059.3:c.5218_5223del is 0.77 (LOG(LR) = −0.26; N = 8 probands). This falls within the ENIGMA neutral zone (>0.48 and <2.08), where neither PP4 nor BP5 is applied.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
PP5	N/A	ENIGMA BRCA2 specification marks PP5 as Not Applicable. ClinVar classification is Uncertain significance (1-star, single submitter), with 9 clinical laboratories reporting VUS and 1 reporting Likely benign. No expert panel review exists. Even under the global PP5/BP6 override (ClinVar 3-star EP → supporting), this does not qualify.
BA1	Not met	ENIGMA BA1 (Stand Alone) requires filter allele frequency (FAF) > 0.1% (FAF > 0.001) in gnomAD non-cancer populations. The grpmax FAF for this variant is 0.000106 (0.0106%), which is below the BA1 threshold.	gnomad_v2 cspec
BS1	Met	The gnomAD v2.1 exome grpmax filter allele frequency (FAF) is 0.000106 (0.0106%), which exceeds the ENIGMA BS1 Strong threshold of FAF > 0.01% (FAF > 0.0001) in non-cancer, non-founder populations. This is observed primarily in the East Asian subpopulation (6/19,916 alleles, AF = 0.030%).	gnomad_v2 cspec
BS2	Not met	ENIGMA BS2 requires observation of the variant in trans with a pathogenic variant in the absence of Fanconi Anemia phenotype, scored via a points system (Specifications Table 8). No such co-occurrence data or phenotype information is available for this variant.	cspec
BS3	Not met	No well-established functional studies demonstrate a neutral effect for this variant. ENIGMA Table 9 (curated functional assays) covers missense and synonymous variants only and does not include this in-frame deletion. Literature review identified no functional studies of this variant.	vcep_specifications_table9_v1_2_2024_11_18 cspec
BS4	Not met	No lack-of-segregation data available for this variant. ENIGMA BS4 requires quantitative co-segregation analysis with LR ≤ 0.48 for Supporting strength.	cspec
BP1	Met	This is an in-frame deletion (p.Leu1740_Ser1741del) located outside the two ENIGMA-defined clinically important functional domains (PALB2 binding aa 10–40; DNA binding aa 2481–3186). SpliceAI predicts no splicing impact (max delta = 0.00, ≤ 0.1). ENIGMA BP1_Strong criteria are satisfied: in-frame deletion outside a clinically important domain with no splicing predicted.	cspec spliceai
BP2	N/A	ENIGMA BRCA2 specification marks BP2 as Not Applicable.
BP3	N/A	ENIGMA BRCA2 specification marks BP3 as Not Applicable.
BP4	Not met	ENIGMA BP4 applies only to missense or in-frame variants located inside a clinically important functional domain with no predicted impact (BayesDel ≤ 0.18 and SpliceAI ≤ 0.1). This variant is at aa 1740–1741, outside the ENIGMA-defined clinically important domains (PALB2 binding aa 10–40; DNA binding aa 2481–3186). The domain location prerequisite is not satisfied.	cspec spliceai
BP5	Not met	Clinical-history likelihood ratio (LR) from Li et al. 2020 (PMID:31853058) is 0.77. This falls within the ENIGMA neutral zone (>0.48 and <2.08), where neither PP4 nor BP5 is applied.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 cspec
BP6	N/A	ENIGMA BRCA2 specification marks BP6 as Not Applicable. ClinVar classification is Uncertain significance (1-star, single submitter). No expert panel benign classification exists. Even under the global PP5/BP6 override, this does not qualify.
BP7	Not met	ENIGMA BP7 applies to (a) intronic/silent variants with mRNA assay evidence of no splicing impact (BP7_Strong RNA), or (b) silent variants inside a clinically important domain if BP4 is met (BP7_Supporting). This is an in-frame deletion, not a silent or intronic variant. No mRNA splicing assay data are available. Neither BP7 pathway applies.	cspec

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