Variant classification summary

NM_000059.3:c.7977-1G>C

BRCA2 · NP_000050.2:p.? · NM_000059.3

GRCh37: chr13:32937315 G>C · GRCh38: chr13:32363178 G>C

Gene: BRCA2 Transcript: NM_000059.3

Final call

Pathogenic

PVS1_Strong PM5_Strong PP4_Moderate PP5_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.7977-1G>C (p.?) variant has been reported in ClinVar as Pathogenic, including a Pathogenic expert-panel classification from ENIGMA.

2

This variant is present at a very low frequency in population databases, with gnomAD v2.1 AF 7.11663e-06 (2/281032 alleles) and gnomAD v4.1 AF 3.10106e-06 (5/1612350 alleles), which is below benign frequency thresholds.

3

RNA studies summarized in the ENIGMA BRCA2 materials reported abnormal splicing for this variant, including exon 18 deletion and exon 17/18 deletion, and ENIGMA Table 4 assigns PVS1_Strong (RNA) at this splice acceptor because variants at this site show leaky splicing.

4

Computational splicing analysis is also strongly abnormal, with a SpliceAI maximum delta score of 0.95, consistent with splice disruption, although this prediction is not counted separately because splice-impact evidence is already captured under PVS1 in the ENIGMA framework.

5

In the BRCA2 clinical-history likelihood-ratio dataset, this variant had an LR of 7.223 across 7 probands, which meets the ENIGMA threshold for PP4 at moderate strength.

Final determination: Pathogenic based on 2 strong pathogenic criteria and 1 moderate pathogenic criterion, which meets the ENIGMA BRCA1/BRCA2 Table 3 pathogenic rule; the additional supporting pathogenic criterion is concordant.

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	Met	This canonical splice acceptor variant in BRCA2 exon 18 is assigned PVS1_Strong (RNA) by the ENIGMA BRCA2 specification. ENIGMA notes that variants at this splice site show leaky splicing, which reduces the weight from very strong to strong; RNA evidence summarized for this variant shows exon 18 deletion and exon 17/18 deletion, supporting an abnormal loss-of-function transcript effect.	cspec pvs1_gene_context pvs1_variant_assessment vcep_specifications_table4_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:16211554
PS1	Not assessed	No independently reviewed pathogenic comparator variant with the same established splicing effect was identified to support PS1. Available evidence supports direct splice disruption for this variant, but the retrieved materials do not establish a separate PS1 comparator-based application.	cspec vcep_specifications_v1_2_2024_11_18
PS2	N/A	This criterion is not applicable in the ENIGMA BRCA2 specification for this review context, and no de novo data were provided.	cspec
PS3	Not met	Available functional evidence is RNA splicing evidence rather than a qualifying protein functional assay. Under the ENIGMA BRCA2 specification, abnormal mRNA-only evidence for this variant is captured under PVS1(RNA), and this variant is not listed in the curated BRCA2 protein functional assay table for PS3.	cspec vcep_specifications_v1_2_2024_11_18 vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001
PS4	Not assessed	This variant has been reported in affected individuals, but no qualifying case-control analysis with an odds ratio and confidence interval meeting the ENIGMA PS4 threshold was identified. The available multifactorial and classification resources do not substitute for a direct PS4 case-control showing.	clinvar vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM1	N/A	PM1 is not used as a separate criterion in the ENIGMA BRCA2 framework for this variant type. This canonical splice-site variant is evaluated through splice-specific criteria rather than domain hotspot evidence.	cspec
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at AF 7.11663e-06 (2/281032 alleles) and in gnomAD v4.1 at AF 3.10106e-06 (5/1612350 alleles), so the ENIGMA requirement for PM2_Supporting of absence from controls is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with another pathogenic BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia. PM3 therefore cannot be assessed from the available evidence.	cspec vcep_specifications_v1_2_2024_11_18
PM4	N/A	PM4 is not applicable because this is not a protein length-changing in-frame deletion, insertion, or stop-loss variant.	cspec
PM5	Met	ENIGMA BRCA2 Table 4 designates exon 18 as eligible for PM5_Strong (PTC). Because this canonical splice variant is assigned PVS1 at exon 18 and ENIGMA applies PM5_PTC at this exon, additional strong pathogenic weight is supported.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	This criterion is not applicable in the ENIGMA BRCA2 specification for this review context, and no assumed de novo observation was provided.	cspec
PP1	Not assessed	No quantitative segregation data were identified for this variant. Without a segregation likelihood ratio meeting ENIGMA thresholds, PP1 cannot be applied.	cspec vcep_specifications_v1_2_2024_11_18
PP2	N/A	PP2 is not applicable in the ENIGMA BRCA2 specification for this variant.	cspec
PP3	N/A	SpliceAI predicts a strong splice effect for this variant with a maximum delta score of 0.95, but PP3 is not separately applied because the same splice-effect evidence is already captured by PVS1 in the ENIGMA framework. The generic PVS1 scaffold for this case also advises against double-counting PP3 for canonical splice variants assessed by PVS1.	cspec spliceai pvs1_variant_assessment
PP4	Met	In the BRCA2 clinical-history likelihood-ratio dataset, this variant has an LR of 7.223 across 7 probands. This exceeds the ENIGMA PP4_Moderate threshold of 4.3 and is below the PP4_Strong threshold of 18.7, supporting PP4 at moderate strength.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 vcep_specifications_v1_2_2024_11_18
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	The observed population frequency is far below the ENIGMA BA1 threshold. gnomAD v4.1 shows grpmax FAF 1.24e-06, which is below the BA1 cutoff of 0.001, so BA1 is not met.	cspec gnomad_v2 gnomad_v4
BS1	Not met	The observed population frequency is below the ENIGMA BS1 thresholds. gnomAD v4.1 shows grpmax FAF 1.24e-06, which is below the BS1_Supporting threshold of 2e-05 and the BS1 threshold of 1e-04, so BS1 is not met.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in individuals scored under the ENIGMA BS2 recessive-disease framework. BS2 therefore cannot be assessed from the available evidence.	cspec vcep_specifications_v1_2_2024_11_18
BS3	Not met	No functional evidence showing normal transcript or normal BRCA2 function was identified for this variant. The available RNA evidence supports abnormal splicing rather than a benign effect, and this variant is not assigned BS3 in the curated ENIGMA functional assay table.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4	Not assessed	No quantitative non-segregation data were identified for this variant. Without a segregation likelihood ratio at or below the ENIGMA BS4 thresholds, BS4 cannot be applied.	cspec vcep_specifications_v1_2_2024_11_18
BP1	N/A	BP1 does not apply because this is not a missense, silent, or in-frame coding variant evaluated under the BRCA2 protein/domain bioinformatic framework. This variant is a canonical splice-site change.	cspec
BP2	N/A	BP2 is not applicable in the ENIGMA BRCA2 specification for this variant.	cspec
BP3	N/A	BP3 is not applicable because this is not an in-frame insertion or deletion in a repetitive region.	cspec
BP4	N/A	BP4 does not apply because this variant is at a native splice acceptor position and computational evidence supports splice disruption rather than no effect. SpliceAI shows a maximum delta score of 0.95, which is far above the ENIGMA no-impact threshold of 0.1.	cspec spliceai bayesdel
BP5	Not met	The clinical-history likelihood ratio does not support BP5. The BRCA2 clinical-history LR for this variant is 7.223, which is above the BP5 benign thresholds of 0.48, 0.23, and 0.05, so BP5 is not met.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 vcep_specifications_v1_2_2024_11_18
BP6	N/A	BP6 is not applicable in this ENIGMA BRCA2 framework.	cspec
BP7	N/A	BP7 does not apply because this is a canonical splice-site variant at the exon 18 acceptor, not a silent or deep intronic variant with evidence for no splicing effect. Available RNA and computational evidence support splice disruption instead of a benign splice outcome.	cspec spliceai vcep_humu_40_1557_s001

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.