Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000059.4(BRCA2):c.663T>G (p.Phe221Leu)

Curation Version - 2.0
Curation History
JSON LD for Version 2.0

CA024240

38058 (ClinVar)

Gene: BRCA2

Condition: BRCA2-related cancer predisposition

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: ff4e802b-b9a8-4835-a0a5-73464acfc89a

Approved on: 2024-06-12

Published on: 2024-06-12

HGVS expressions

NM_000059.4:c.663T>G

NM_000059.4(BRCA2):c.663T>G (p.Phe221Leu)

NC_000013.11:g.32329474T>G

CM000675.2:g.32329474T>G

NC_000013.10:g.32903611T>G

CM000675.1:g.32903611T>G

NC_000013.9:g.31801611T>G

NG_012772.3:g.18995T>G

ENST00000470094.2:c.663T>G

ENST00000528762.2:c.663T>G

ENST00000530893.7:c.294T>G

ENST00000665585.2:c.663T>G

ENST00000666593.2:c.663T>G

ENST00000700202.2:c.663T>G

ENST00000700201.1:c.*442T>G

ENST00000380152.8:c.663T>G

ENST00000544455.6:c.663T>G

ENST00000614259.2:c.663T>G

ENST00000680887.1:c.663T>G

ENST00000380152.7:c.663T>G

ENST00000530893.6:n.861T>G

ENST00000544455.5:c.663T>G

ENST00000614259.1:n.663T>G

NM_000059.3:c.663T>G

Likely Benign

BP1_Strong

BP5 BA1 PP4 PM2 BS1

Evidence Links 0

Expert Panel

ENIGMA BRCA1 and BRCA2 VCEP

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.663T>G variant in BRCA2 is a missense variant predicted to cause substitution of Phenylalanine by Leucine at amino acid 221 (p.Phe221Leu). 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 missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0, score threshold <0.1) (BP1_Strong met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.396 (based on Co-occurrence LR=1.08; Family History LR=1.3), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Likely benign variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (BP1_Strong).

BP1_Strong

This missense variant is located outside of a key functional domain and was not predicted to alter mRNA splicing using the SpliceAI predictor (score 0, score threshold <0.1) (BP1_Strong met).

BP5

Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.396 (based on Co-occurrence LR=1.08; Family History LR=1.3), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31131967).

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).

PP4

PM2

BS1

Curation History

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.