The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!


Variant: NM_000059.4(BRCA2):c.632-3C>G

CA348611

219896 (ClinVar)

Gene: BRCA2
Condition: BRCA2-related cancer predisposition
Inheritance Mode: Autosomal dominant inheritance
UUID: a1d2a9d9-1471-4b81-90ac-a0c1e0672210
Approved on: 2024-06-12
Published on: 2024-06-12

HGVS expressions

NM_000059.4:c.632-3C>G
NM_000059.4(BRCA2):c.632-3C>G
NC_000013.11:g.32329440C>G
CM000675.2:g.32329440C>G
NC_000013.10:g.32903577C>G
CM000675.1:g.32903577C>G
NC_000013.9:g.31801577C>G
NG_012772.3:g.18961C>G
ENST00000470094.2:c.632-3C>G
ENST00000528762.2:c.632-3C>G
ENST00000530893.7:c.263-3C>G
ENST00000665585.2:c.632-3C>G
ENST00000666593.2:c.632-3C>G
ENST00000700202.2:c.632-3C>G
ENST00000700201.1:c.*411-3C>G
ENST00000380152.8:c.632-3C>G
ENST00000544455.6:c.632-3C>G
ENST00000614259.2:c.632-3C>G
ENST00000680887.1:c.632-3C>G
ENST00000380152.7:c.632-3C>G
ENST00000530893.6:n.830-3C>G
ENST00000544455.5:c.632-3C>G
ENST00000614259.1:n.632-3C>G
NM_000059.3:c.632-3C>G

Likely Pathogenic

Met criteria codes 3
PM3 PP4_Moderate PVS1_Moderate
Not Met criteria codes 3
BA1 PM2 BS1

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA2 Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
ENIGMA BRCA1 and BRCA2 VCEP
The c.632-3C>G variant is an intronic variant occurring in intron 7 of the BRCA2 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by creating a new acceptor splice site, resulting in retention of 2bp from intron 7, which leads to a frameshift and generates a premature stop codon (PMIDs: 30883759, 32123317, 22505045). Reduced expression of aberrant transcript reported by one assay suggesting potential incomplete expression of the aberrant transcript (Ambry internal contributor). Appropriate code strength determined by comparison of results to PVS1 decision tree PVS1 (RNA) was downgraded to PVS1_Moderate (RNA). This variant has been detected in 2 siblings with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least two clinical features of FA (physical features, pathology findings and cancer diagnosis ≤5yr) and confirmed chromosome breakage, are seen in these individuals. Both siblings were homozygous for the variant. Total points equated to 2 (PM3 met; PMID: 25381700). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 12.477 (based on Pathology LR=1.07; Co-occurrence LR=1.0498; Family History LR=11.107), within the thresholds for Moderate evidence towards pathogenicity (LR >4.3 & ≤18.7) (PP4_Moderate met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1_Moderate (RNA), PM3, PP4_Moderate).
Met criteria codes
PM3
This variant has been detected in 2 siblings with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least two clinical features of FA (physical features, pathology findings and cancer diagnosis ≤5yr) and confirmed chromosome breakage, are seen in these individuals. Both siblings were homozygous for the variant. Total points equated to 2 (PM3 met; PMID: 25381700).
PP4_Moderate
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 12.477 (based on Pathology LR=1.07; Co-occurrence LR=1.0498; Family History LR=11.107), within the thresholds for Moderate evidence towards pathogenicity (LR >4.3 & ≤18.7) (PP4_Moderate met; PMID: 31131967).
PVS1_Moderate
This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by creating a new acceptor splice site, resulting in retention of 2bp from intron 7, which leads to a frameshift and generates a premature stop codon (PMIDs: 30883759, 32123317, 22505045). Reduced expression of aberrant transcript reported by one assay suggesting potential incomplete expression of the aberrant transcript (Ambry internal contributor). Appropriate code strength determined by comparison of results to PVS1 decision tree PVS1 (RNA) was downgraded to PVS1_Moderate (RNA).
Not Met criteria codes
BA1
This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met).
PM2
This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met).
BS1
This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met).
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