Evidence Repository
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 computed assertion could be determined for this classification!

Variant: NM_000059.4(BRCA2):c.316G>A (p.Gly106Arg)

CA017418

185084 (ClinVar)

Gene: BRCA2 (HGNC:675)
Condition: BRCA2-related cancer predisposition (MONDO:0700269)
Inheritance Mode: Autosomal dominant inheritance
UUID: 6371fabd-245a-4c40-87b6-dbf1d91d6416
Approved on: 2025-12-03
Published on: 2025-12-02

HGVS expressions

NM_000059.4(BRCA2):c.316G>A (p.Gly106Arg)
NM_000059.4:c.316G>A
NC_000013.11:g.32319325G>A
CM000675.2:g.32319325G>A
NC_000013.10:g.32893462G>A
CM000675.1:g.32893462G>A
NC_000013.9:g.31791462G>A
NG_012772.3:g.8846G>A
NG_017006.2:g.1039C>T
ENST00000470094.2:c.316G>A
ENST00000528762.2:c.316G>A
ENST00000530893.7:c.-54G>A
ENST00000665585.2:c.316G>A
ENST00000666593.2:c.316G>A
ENST00000700202.2:c.316G>A
ENST00000700200.1:n.191+2798G>A
ENST00000700201.1:c.316G>A
ENST00000380152.8:c.316G>A
ENST00000544455.6:c.316G>A
ENST00000614259.2:c.316G>A
ENST00000680887.1:c.316G>A
ENST00000380152.7:c.316G>A
ENST00000530893.6:n.514G>A
ENST00000544455.5:c.316G>A
ENST00000614259.1:n.316G>A
NM_000059.3:c.316G>A
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Uncertain Significance

Met criteria codes 2
PP3 PM3
Not Met criteria codes 8
BA1 BS3 BS1 BP7 BP5 PS3 PP4 PM2

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 1.1.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
ENIGMA BRCA1 and BRCA2 VCEP
The c.316G>A variant in BRCA2 is a missense variant predicted to cause substitution of Glycine by Arginine at amino acid 106 (p.(Gly106Arg)). 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). Missense variant shown to alter splicing (see PVS1 or BP7 for description), functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study to exhibit a partial impact on protein function, between what was observed for benign and pathogenic control variants (PMID:32641407) (PS3 and BS3 not met). This BRCA2 missense variant has a SpliceAI score of 0.29, predicting an impact on splicing (score threshold >0.20) (PP3 met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.54 (based on Family History LR=1.54), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058). This is a missense variant outside a key functional domain, and mRNA experimental analysis indicates production of a sufficient amount of wildtype transcript (PMID: 32641407), however the VCEP decided to currently not apply BP7_Strong (RNA) due to the results being close to the threshold (~30% WT or assumed functional transcript). This variant has been detected in an individual 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 this individual. They were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (BRCA2:c.2808_2811del), confirmed to be in trans. Total points equated to 2 (PM3 met; PMIDs: 32641407, 36721989). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PP3, PM3).
Met criteria codes
PP3
This BRCA2 missense variant has a SpliceAI score of 0.29, predicting an impact on splicing (score threshold >0.20) (PP3 met).
PM3
This variant has been detected in an individual 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 this individual. They were compound heterozygous for the variant and a pathogenic or likely pathogenic variant (BRCA2:c.2808_2811del), confirmed to be in trans. Total points equated to 2 (PM3 met; PMIDs: 32641407, 36721989).
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).
BS3
Missense variant shown to alter splicing (see PVS1 or BP7 for description), functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study to exhibit a partial impact on protein function, between what was observed for benign and pathogenic control variants (PMID:32641407) (PS3 and BS3 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).
BP7
This is a missense variant outside a key functional domain, and mRNA experimental analysis indicates production of a sufficient amount of wildtype transcript (PMID: 32641407), however the VCEP decided to currently not apply BP7_Strong (RNA) due to the results being close to the threshold (~30% WT or assumed functional transcript).
BP5
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.54 (based on Family History LR=1.54), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058).
PS3
Missense variant shown to alter splicing (see PVS1 or BP7 for description), functional data considered only from assays that measure effect via mRNA and protein. Reported by one calibrated study to exhibit a partial impact on protein function, between what was observed for benign and pathogenic control variants (PMID:32641407) (PS3 and BS3 not met).
PP4
Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.54 (based on Family History LR=1.54), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058).
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).
Curation History
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