Variant classification summary

NM_000059.4:c.8023A>G

BRCA2 · NP_000050.3:p.(Ile2675Val) · NM_000059.4

GRCh37: chr13:32937362 A>G · GRCh38: chr13:32363225 A>G

Gene: BRCA2 Transcript: NM_000059.4

Final call

Pathogenic

PP1_VeryStrong PP3_Supporting PP5_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.(Ile2675Val)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The BRCA2 c.8023A>G (p.Ile2675Val) variant has not been observed in COSMIC and has been reported in ClinVar as pathogenic, including an expert-panel pathogenic classification from the ClinGen ENIGMA BRCA1/2 Variant Curation Expert Panel.

2

This variant is present at very low frequency in gnomAD, with 1/251076 alleles in v2.1 and 1/1614050 alleles in v4.1; the highest observed population frequencies are 5.44e-05 in East Asian individuals in v2.1 and 2.23e-05 in East Asian individuals in v4.1, so the variant is rare but not absent from controls.

3

BRCA2 multifactorial data show strong pathogenic evidence for this variant, including a segregation likelihood ratio of 605.14 and a posterior probability of 0.999651, and multiple splicing studies reported complete 309-nt skipping of exon 18 with no full-length transcript detected from the variant allele.

4

Computational splicing analysis supports a deleterious effect, with a SpliceAI maximum delta score of 0.99, which is above the ENIGMA PP3 threshold of 0.2 and well above the benign BP4 threshold of 0.1.

Final determination: ENIGMA BRCA1/2 Table 3 supports a Pathogenic classification because one very strong pathogenic criterion and two supporting pathogenic criteria are met.

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	Not assessed	Multiple RNA studies reported complete 309-nt skipping of BRCA2 exon 18 with no full-length transcript detected from the variant allele, but this exonic substitution is outside the default generic null-variant buckets and no explicit ENIGMA RNA-based PVS1 strength assignment for this specific variant was identified in the retrieved materials. Manual review is needed to determine whether the observed splicing effect warrants PVS1(RNA) and at what strength.	cspec pvs1_gene_context pvs1_variant_assessment vcep_humu_40_1557_s001 PMID:18424508 PMID:22505045
PS1	Not assessed	No retrieved evidence identified a different BRCA2 variant with the same protein change or the same established splicing consequence that has already been classified as pathogenic or likely pathogenic for PS1 application.	cspec
PS2	N/A	No de novo framework is used for BRCA2 in this specification for this case, and no confirmed de novo data were identified.	cspec
PS3	Not assessed	Available studies for this variant assess abnormal splicing rather than a calibrated protein-function assay entry in the ENIGMA functional table. Under the BRCA2 specification, mRNA-only damaging evidence is considered under PVS1(RNA) rather than PS3.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:18424508 PMID:22505045
PS4	Not assessed	A qualifying case-control comparison was not identified. In the BRCA2 multifactorial dataset, the case-control likelihood ratio for this variant was not reported, so the retrieved evidence does not establish the ENIGMA PS4 requirement for significantly increased prevalence in affected individuals versus controls.	cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PM1	N/A	PM1 is not used for BRCA2 in this specification.	cspec
PM2	Not met	This variant is not absent from controls. It is present in gnomAD v2.1 at 1/251076 alleles (AF 3.98e-06) and in gnomAD v4.1 at 1/1614050 alleles (AF 6.20e-07), so the ENIGMA PM2_Supporting requirement for absence from gnomAD is not met.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified for this variant in trans with another BRCA2 variant in an individual with BRCA2-related Fanconi anemia, so PM3 could not be evaluated.	cspec
PM4	N/A	PM4 is not used for BRCA2 in this specification.	cspec
PM5	N/A	In this BRCA2 specification, PM5 is defined for protein-terminating variants in eligible exons. This variant is a single-nucleotide substitution annotated at the protein level as p.(Ile2675Val), so PM5 is not applicable under the retrieved BRCA2 rule set.	cspec vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	PM6 is not used for BRCA2 in this specification for this case context.	cspec
PP1	Met	Quantitative co-segregation evidence supports pathogenicity. The BRCA2 multifactorial dataset reports a segregation likelihood ratio of 605.14 for this variant, which is above the ENIGMA PP1_Very Strong threshold of 350.	cspec vcep_humu_40_1557_s001
PP2	N/A	PP2 is not used for BRCA2 in this specification.	cspec
PP3	Met	Computational evidence supports a deleterious splicing effect. SpliceAI predicts strong splice impact with a maximum delta score of 0.99, which is above the ENIGMA PP3 threshold of 0.2.	cspec spliceai
PP4	Not assessed	No variant-specific clinical-history likelihood ratio was identified in the BRCA2 clinical-history table, so PP4 could not be assigned from the retrieved evidence. Legacy multifactorial data exist, but applying those here as PP4 would risk double counting with segregation-based evidence.	cspec vcep_pmid_31853058_brca2_clinical_history_lr vcep_humu_40_1557_s001 PMID:31853058
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant does not meet the ENIGMA BA1 frequency threshold. The highest observed population frequency in gnomAD is 5.44e-05 in East Asian individuals in v2.1 and 2.23e-05 in East Asian individuals in v4.1, both well below the BA1 requirement of filter allele frequency greater than 0.001.	cspec gnomad_v2 gnomad_v4
BS1	Not met	The retrieved gnomAD records do not show a qualifying filter allele frequency for BS1, and the observed frequencies do not justify direct BS1 assignment from the available evidence. The highest observed population frequency is 5.44e-05 in gnomAD v2.1 East Asian and 2.23e-05 in gnomAD v4.1 East Asian, while group-max FAF was not available in the retrieved gnomAD outputs.	cspec gnomad_v2 gnomad_v4
BS2	Not assessed	No proband-level evidence was identified to show this variant in individuals without features of BRCA2-related Fanconi anemia, so BS2 could not be evaluated.	cspec
BS3	Not assessed	No variant-specific benign functional assignment was identified in the ENIGMA functional assay table. Available studies for this variant show abnormal splicing rather than normal function, so BS3 is not supported by the retrieved evidence.	cspec vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001
BS4	Not met	Available segregation data do not support lack of segregation. The BRCA2 multifactorial dataset reports a segregation likelihood ratio of 605.14 in favor of pathogenicity, which is far above the BS4 thresholds that require a likelihood ratio of 0.48 or lower against pathogenicity.	cspec vcep_humu_40_1557_s001
BP1	Not met	This missense variant does not meet BP1. It lies within the BRCA2 DNA-binding domain and SpliceAI predicts splice disruption with a score of 0.99, whereas ENIGMA BP1_Strong requires a variant outside a clinically important domain and no predicted splicing impact with SpliceAI 0.1 or lower.	cspec spliceai
BP2	N/A	BP2 is not used for BRCA2 in this specification.	cspec
BP3	N/A	BP3 is not used for BRCA2 in this specification.	cspec
BP4	Not met	This variant does not meet BP4 because computational evidence predicts splice disruption. SpliceAI gives a maximum delta score of 0.99, which is above the ENIGMA BP4 requirement for no predicted splice impact with SpliceAI 0.1 or lower.	cspec spliceai
BP5	Not assessed	No variant-specific clinical-history likelihood ratio in the benign direction was identified in the BRCA2 clinical-history table, so BP5 could not be assigned from the retrieved evidence.	cspec vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058
BP6	N/A	BP6 is not used in this framework.	cspec
BP7	N/A	BP7 is intended for silent or intronic variants, or for specific RNA-based benign scenarios. This is a missense variant with predicted and observed splice disruption, so BP7 is not applicable.	cspec spliceai vcep_humu_40_1557_s001

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