NM_000059.4:c.632-3C>G

BRCA2 · NP_000050.3:p.? · NM_000059.4

GRCh37: chr13:32903577 C>G · GRCh38: chr13:32329440 C>G

Gene: BRCA2 Transcript: NM_000059.4

Final call

Variant details

Gene

BRCA2

Transcript

NM_000059.4

Protein

NP_000050.3:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The BRCA2 c.632-3C>G (NP_000050.3:p.?) variant has been reported in ClinVar and is classified as Likely Pathogenic by the ClinGen ENIGMA BRCA1/2 expert panel.

This variant is rare in population databases, with 1/243142 alleles in gnomAD v2.1 (AF 0.00041%) and 4/1590500 alleles in gnomAD v4.1 (AF 0.00025%), which is below ENIGMA BA1 and BS1 thresholds but does not meet the absence requirement for PM2.

RNA splicing studies reported complete splice disruption with retention of 2 intronic bases and no wild-type transcript detected from the variant allele, which is consistent with an RNA-based loss-of-function effect and supports PVS1_Strong (RNA) under the ENIGMA BRCA2 framework.

In silico splicing prediction also supports a spliceogenic effect, with SpliceAI max delta score 0.95, well above the ENIGMA PP3 splice threshold of 0.2, although PP3 is not scored separately when PVS1 is met.

Final determination: PVS1_Strong plus one supporting pathogenic criterion does not meet the ENIGMA Table 3 threshold for likely pathogenic or pathogenic classification; therefore the variant is classified as Uncertain significance.

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 intronic variant is outside the canonical ±1,2 splice positions, but RNA studies identified complete splice disruption with retention of 2 intronic bases and no wild-type transcript detected from the variant allele. Under the ENIGMA BRCA2 splicing framework, mRNA-only evidence for a noncanonical splice variant with apparent near-complete aberrant splicing supports PVS1 at RNA-adjusted strength rather than PS3.	vcep_specifications_v1_2_2024_11_18 vcep_appendices_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:22505045
PS1	Not assessed	No directly matched pathogenic or likely pathogenic reference variant with the same predicted splicing event was identified from the reviewed evidence, so PS1 was not assessed.	vcep_specifications_v1_2_2024_11_18
PS2	N/A	No de novo data were identified, and this criterion is not used in the BRCA2 ENIGMA specification for this evidence set.	vcep_specifications_v1_2_2024_11_18
PS3	Not met	Available functional evidence is an mRNA splicing assay rather than a protein function assay. Under the ENIGMA BRCA2 specification, damaging mRNA-only evidence is captured under PVS1 (RNA) rather than PS3.	vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:22505045
PS4	Not assessed	No qualifying case-control odds ratio or proband-counting evidence meeting ENIGMA PS4 requirements was identified for this variant. Multifactorial observations were reviewed, but those data are not sufficient on their own to assign PS4 here.	vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001
PM1	N/A	This is an intronic splice-region variant, and PM1 is not applicable in the BRCA2 ENIGMA specification for this type of evidence.	vcep_specifications_v1_2_2024_11_18
PM2	Not met	This variant is not absent from population databases. It is present in gnomAD v2.1 at 1/243142 alleles (AF 0.00041%) and in gnomAD v4.1 at 4/1590500 alleles (AF 0.00025%), so the ENIGMA PM2_Supporting absence requirement is not met.	gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
PM3	Not assessed	No evidence was identified for this variant occurring with another BRCA2 variant in a patient with BRCA2-related Fanconi anemia, so PM3 was not assessed.	vcep_specifications_v1_2_2024_11_18
PM4	N/A	PM4 is not applicable under the BRCA2 ENIGMA specification for this variant context.	vcep_specifications_v1_2_2024_11_18
PM5	N/A	This variant is not a protein-terminating variant and no applicable PM5 comparator evidence was identified, so PM5 was not applied.	vcep_specifications_v1_2_2024_11_18 vcep_specifications_table4_v1_2_2024_11_18
PM6	N/A	No assumed de novo evidence was identified, and this criterion is not used in the BRCA2 ENIGMA specification for this evidence set.	vcep_specifications_v1_2_2024_11_18
PP1	Not assessed	No quantitative co-segregation data were identified for this variant, so PP1 was not assessed.	vcep_specifications_v1_2_2024_11_18
PP2	N/A	PP2 is not applicable under the BRCA2 ENIGMA specification.	vcep_specifications_v1_2_2024_11_18
PP3	Not met	SpliceAI predicts a strong splice effect for this variant (max delta score 0.95, above the PP3 threshold of 0.2), but the ENIGMA BRCA2 specification states that PP3 should not be applied when PVS1 is met at any strength. Predictive evidence is therefore noted but not scored separately.	spliceai vcep_specifications_v1_2_2024_11_18
PP4	Not met	Clinical-history likelihood data do not reach the ENIGMA PP4 threshold. The variant-specific BRCA2 clinical-history LR is 1.63 from 3 probands, which is below the supporting threshold of 2.08.	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 Likely pathogenic.	vcep_specifications_v1_2_2024_11_18 clinvar
BA1	Not met	Population frequency does not meet the ENIGMA BA1 threshold. The gnomAD v4.1 filter allele frequency is 0.00001752, which is below the BA1 threshold of 0.001, and the observed allele counts are low.	gnomad_v4 vcep_specifications_v1_2_2024_11_18
BS1	Not met	Population frequency does not meet the ENIGMA BS1 threshold. The highest available filter allele frequency is 0.00001752 in gnomAD v4.1, which is below the supporting threshold of 0.00002 and well below the strong threshold of 0.0001.	gnomad_v2 gnomad_v4 vcep_specifications_v1_2_2024_11_18
BS2	Not assessed	No evidence was identified showing this variant in trans with another BRCA2 variant in individuals lacking Fanconi anemia features, so BS2 was not assessed.	vcep_specifications_v1_2_2024_11_18
BS3	Not met	No benign protein-function evidence was identified for this variant. The available assay evidence shows splice disruption and is captured under PVS1 (RNA), not BS3.	vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:22505045
BS4	Not assessed	No quantitative lack-of-segregation evidence was identified for this variant, so BS4 was not assessed.	vcep_specifications_v1_2_2024_11_18
BP1	Not met	This criterion is not met because the variant is intronic and predicted to alter splicing. BP1 in BRCA2 is reserved for silent, missense, or in-frame variants outside critical domains with no predicted splice impact.	spliceai vcep_specifications_v1_2_2024_11_18
BP2	N/A	BP2 is not applicable under the BRCA2 ENIGMA specification.	vcep_specifications_v1_2_2024_11_18
BP3	N/A	BP3 is not applicable under the BRCA2 ENIGMA specification.	vcep_specifications_v1_2_2024_11_18
BP4	Not met	This criterion is not met because computational evidence predicts splice disruption. SpliceAI is 0.95, which is above the BP4 no-splicing-impact threshold of 0.1.	spliceai vcep_specifications_v1_2_2024_11_18
BP5	Not met	Clinical-history likelihood data do not meet ENIGMA BP5 thresholds. The variant-specific BRCA2 clinical-history LR is 1.63, which is above the BP5 supporting threshold of 0.48 and therefore does not support a benign clinical-history code.	vcep_pmid_31853058_brca2_clinical_history_lr PMID:31853058 vcep_specifications_v1_2_2024_11_18
BP6	N/A	BP6 is not applicable under the BRCA2 ENIGMA specification.	vcep_specifications_v1_2_2024_11_18
BP7	Not met	This criterion is not met because the variant is at position c.632-3, which is not outside the low-conservation intronic region used for BP7 in BRCA2, and both prediction and RNA evidence show splice disruption rather than no impact. SpliceAI is 0.95, far above the BP7/BP4 no-impact threshold of 0.1.	spliceai vcep_specifications_v1_2_2024_11_18 vcep_humu_40_1557_s001 PMID:22505045

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