NM_000059.3:c.8023A>G

BRCA2 · NP_000050.2:p.(Ile2675Val) · NM_000059.3

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

Gene: BRCA2 Transcript: NM_000059.3

Final call

Pathogenic

PP1_VeryStrong PP3_Supporting PP4_Supporting PP5_Supporting

Variant details

Gene

BRCA2

Transcript

NM_000059.3

Protein

NP_000050.2:p.(Ile2675Val)

gnomAD AF

6.195594932003346e-07 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA2 c.8023A>G (p.Ile2675Val) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic by the ClinGen ENIGMA BRCA1/2 expert panel.

This variant is present at very low frequency in population databases, with 1/251076 alleles in gnomAD v2.1 and 1/1614050 alleles in gnomAD v4.1, with no homozygotes reported.

In published splice studies summarized in the ENIGMA-aligned BRCA resource, this variant generated a strong donor site within exon 18 and was associated with a predominant exon 18-deleted transcript; the multifactorial dataset also shows a segregation likelihood ratio of 605.14 and an overall posterior probability of pathogenicity of 0.999651.

Computational evidence supports splice disruption, with SpliceAI 0.99 exceeding the BRCA2 ENIGMA PP3 threshold of 0.2; REVEL is high at 0.88, while BayesDel is 0.086 and does not support a benign BP4 call because SpliceAI is above the BP4 threshold of 0.1.

Final determination: Pathogenic based on 1 very strong pathogenic criterion and at least 2 supporting pathogenic criteria under the ENIGMA BRCA1/BRCA2 Table 3 combining rules.

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 met	RNA studies identified a predominant in-frame exon 18 deletion transcript for this variant, but the available evidence does not show a canonical null allele or provide a clear ENIGMA PVS1(RNA) weight for this specific event. Available evidence therefore does not support applying PVS1 at this time.	vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:18424508 PMID:22505045
PS1	Not met	No qualifying previously classified pathogenic or likely pathogenic comparator with the same proven protein or splicing consequence was identified for PS1 application.	cspec
PS2	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PS3	Not met	Published evidence shows abnormal splicing rather than a calibrated protein-function assay result for this variant. Under the BRCA2 ENIGMA specification, mRNA-only damaging evidence is considered under PVS1(RNA) rather than PS3, and no qualifying Table 9 PS3 assignment was identified.	vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:18424508 PMID:22505045 cspec
PS4	Not assessed	Multifactorial pathogenic evidence was identified for this variant, but no direct case-control odds ratio with p-value meeting the BRCA2 ENIGMA PS4 threshold was extracted from the retrieved evidence. PS4 was therefore not assessed.	cspec vcep_humu_40_1557_s001 vcep_supplementarytables_v1_2_2024_11_18
PM1	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PM2	Not met	This variant is not absent from population databases. 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 requirement for absence from controls is not met.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No evidence was identified showing this variant in trans with another pathogenic BRCA2 variant in an individual with a phenotype consistent with BRCA2-related Fanconi anemia. PM3 was not assessed.	cspec
PM4	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PM5	N/A	For BRCA2 ENIGMA, PM5 is repurposed for truncating or protein-termination-codon logic rather than classic same-residue missense comparison. This missense variant is therefore not eligible for PM5.	cspec pm5_candidates
PM6	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PP1	Met	This variant shows strong segregation with disease. The quantitative segregation likelihood ratio is 605.14, which is above the ENIGMA PP1_Very Strong threshold of 350.	vcep_humu_40_1557_s001 PMID:17924331 cspec
PP2	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
PP3	Met	Computational evidence supports a splice-altering effect. SpliceAI predicts a strong splice impact with a maximum delta score of 0.99, which is above the ENIGMA PP3 threshold of 0.2 for predicted splicing impact.	spliceai cspec revel bayesdel
PP4	Met	Clinical-history evidence is in the pathogenic direction. The family-history likelihood ratio is 2.88, which is above the ENIGMA PP4 threshold of 2.08 and below the moderate threshold of 4.3, supporting PP4 at supporting strength.	vcep_humu_40_1557_s001 PMID:17924331 cspec
PP5	Met	Expert panel ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	Population frequency does not reach the ENIGMA BA1 threshold. 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, both below the BA1 threshold of 0.001.	gnomad_v2 gnomad_v4 cspec
BS1	Not assessed	This variant is present at a very low frequency in gnomAD, but the retrieved data did not provide a qualifying ENIGMA filter allele frequency value for BS1 assessment. BS1 was therefore not assessed.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	No qualifying observations were identified showing this variant in individuals without features of BRCA2-related Fanconi anemia under the ENIGMA BS2 framework.	cspec
BS3	Not met	Available functional evidence does not show normal or retained function. Instead, RNA studies reported abnormal splicing with exon 18 deletion, and no qualifying benign Table 9 BS3 assignment was identified.	vcep_specifications_table9_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:18424508 PMID:22505045
BS4	Not met	Available segregation evidence is in favor of pathogenicity rather than lack of segregation. The segregation likelihood ratio is 605.14, whereas ENIGMA BS4 requires a likelihood ratio of 0.48 or lower for benign evidence.	vcep_humu_40_1557_s001 PMID:17924331 cspec
BP1	Not met	This missense variant does not meet BRCA2 ENIGMA BP1 because it is not a low-risk missense change without splice concern. SpliceAI predicts strong splice impact with a score of 0.99, which is above the BP1 requirement for no predicted splicing impact at 0.1 or lower.	spliceai cspec
BP2	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
BP3	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
BP4	Not met	Computational evidence does not support BP4. Although the BayesDel score is 0.086 and below the BRCA2 no-impact threshold of 0.18, SpliceAI is 0.99, which is above the BP4 requirement for no predicted splice impact at 0.1 or lower.	bayesdel spliceai cspec
BP5	Not met	Available clinical-history evidence is not in the benign direction. The family-history likelihood ratio is 2.88, which is above 1 and above the benign BP5 threshold of 0.48.	vcep_humu_40_1557_s001 PMID:17924331 cspec
BP6	N/A	This criterion is not used in the BRCA2 ENIGMA specification.	cspec
BP7	Not met	This is a missense variant with predicted splice impact rather than a synonymous or eligible intronic change with no splice effect, so BP7 is not met.	spliceai cspec

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.