BRCA2 c.8303T>A, p.Leu2768His
NM_000059.4:c.8303T>A
Variant of Uncertain Significance (VUS)
Strong functional evidence of no damaging effect (BS3) combined with absence from population (PM2) and supporting computational evidence (PP3) outweighs the moderate PM5. The net evidence supports a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
PM5
PP3
BS3
Genetic Information
Gene & Transcript Details
Gene
BRCA2
Transcript
NM_000059.4
MANE Select
Total Exons
27
Strand
Forward (+)
Reference Sequence
NC_000013.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000059.2 | Alternative | 27 exons | Forward |
| NM_000059.3 | RefSeq Select | 27 exons | Forward |
Variant Details
HGVS Notation
NM_000059.4:c.8303T>A
Protein Change
L2768H
Location
Exon 18
(Exon 18 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 2768: L2768P
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.8303T>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
6 publications
Uncertain Significance (VUS)
Based on 8 submitter reviews in ClinVar
Submitter Breakdown
7 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (6)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 2768 of the BRCA2 protein (p.Leu2768His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25452441). ClinVar contains an entry for this variant (Variation ID: 142807). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 33609447) indicates that this missense variant is not expected to disrupt BRCA2 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 29394989, 35736817). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
This missense variant replaces leucine with histidine at codon 2768 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. Functional studies have reported that this variant does not deleteriously impact BRCA2 function on a homology-mediated DNA repair assay (PMID: 29394989, 35736817) and loss-of-function in cisplatin and PARP inhibitor sensitivity assays using a humanized mouse embryonic stem cell model (PMID: 37713444). This variant has been reported in at least one individual affected with breast cancer (PMID: 25452441) and in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000815). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Variant summary: BRCA2 c.8303T>A (p.Leu2768His) results in a non-conservative amino acid change located in the BRCA2, OB1 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 248454 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8303T>A has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer (Couch_2015). This report does not provide an unequivocal conclusion about association of the variant with Hereditary Breast and Ovarian Cancer. A functional study, Guidugli_2018, found the variant to not significantly impede homology-directed DNA repair activity. Five ClinVar submissions (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (1 clinical laboratories) and as Uncertain significance (7 clinical laboratories) and as Uncertain Significance (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
ClinVar reports other pathogenic variants at position 2768: L2768P
PM5 criterion applied.
Functional Summary
The BRCA2 L2768H variant has been functionally characterized and is likely neutral. In vitro studies using a homology-directed DNA repair (HDR) assay demonstrated that the variant's DNA-repair activity is comparable to that of wildtype BRCA2, indicating no significant impact on protein function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
REVEL Score
0.773
0.773
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
Yes
Additional Predictors
Pathogenic:
polyphen_prediction: probably_damagingmetasvm: Dmetalr: D
Benign:
CADD: 4.92primateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, PVS1 applies to null variants (nonsense, frameshift, canonical ±1/2 splice) in genes where LOF is disease mechanism; this is a missense change. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when the same amino acid change as a known pathogenic variant occurs; no such prior pathogenic L2768H is reported. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG rules, PS2 requires confirmed de novo occurrence; parental data are not available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 applies where well-established functional studies show damaging effect; the HDR assay shows wild-type activity. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires significant case-control enrichment; no case-control data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG rules, PM1 applies to variants in mutational hotspots or functional domains without benign variation; this residue is within the DNA-binding domain but not a defined hotspot per VCEP. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2 Supporting: "Absent from controls in an outbred population..."; this variant is absent from gnomAD. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies for Fanconi Anemia phenotype with trans variants; no FA phenotype or trans variant data are available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG rules, PM4 applies to protein length changes; this is a missense variant. Therefore, this criterion is not applied.
PM5
PM5 (Moderate)
According to standard ACMG rules, PM5 Moderate: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen"; another pathogenic variant at residue L2768 has been reported. Therefore, PM5 is applied at Moderate strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG rules, PM6 applies to presumed de novo without confirmation; no such data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires segregation in multiple affected family members; no segregation data are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG rules, PP2 applies for missense in genes with low benign variation; BRCA2 has many benign missense. Therefore, this criterion is not applied.
PP3
PP3 (Supporting)
According to VCEP guidelines, PP3 Supporting: "Apply PP3 for missense...inside a clinically important functional domain...predicted impact via protein change"; L2768H lies in the DNA-binding domain and REVEL=0.77. Therefore, PP3 is applied at Supporting strength.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 requires phenotype specificity and multifactorial likelihood; no detailed clinical data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG rules, PP5 (reputable source) is not used if evidence is not independent; ClinVar assertions are mixed. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 Stand-Alone applies if allele frequency >0.1%; this variant is absent. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies if allele frequency >0.01%; this variant is absent. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies for observation in healthy adults without FA features; no such data. Therefore, this criterion is not applied.
BS3
BS3 (Strong)
According to VCEP guidelines, BS3 Strong: "Well-established in vitro functional studies show no damaging effect"; the HDR assay shows wild-type function. Therefore, BS3 is applied at Strong strength.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation; no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 applies to missense outside functional domains; this is inside the DNA-binding domain. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG rules, BP2 applies when observed in trans with a pathogenic variant in dominant disease; no such data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG rules, BP3 applies to in-frame indels in repetitive regions; not relevant to this missense. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 applies to benign computational predictions; here multiple tools are conflicting, and REVEL supports deleterious. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 requires co-occurrence with other pathogenic variants with no phenotype; no such data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG rules, BP6 applies to benign assertions from reputable sources without evidence; no such independent assertion. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to silent or intronic variants with no impact; this is missense. Therefore, this criterion is not applied.