BRCA2 c.2606C>T, p.Ser869Leu
NM_000059.4:c.2606C>T
COSMIC ID: COSM6934081
Variant of Uncertain Significance (VUS)
The variant meets BS1_Strong based on allele frequency exceeding the VCEP threshold for benign. No pathogenic criteria apply. Therefore, NM_000059.4:c.2606C>T (S869L) in BRCA2 is classified as Likely Benign.
ACMG/AMP Criteria Applied
BS1
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.2606C>T
Protein Change
S869L
Location
Exon 11
(Exon 11 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 869: S869X
Alternate Identifiers
COSM6934081
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.2606C>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000451%
Extremely Rare
Highest in Population
European (non-Finnish)
0.000947%
Very Rare
Global: 0.000451%
European (non-Finnish): 0.000947%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 221518Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000451%, 1/221518 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.000947%, 1/105576 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
4 publications
Uncertain Significance (VUS)
Based on 9 submitter reviews in ClinVar
Submitter Breakdown
5 VUS
4 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely benign. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with BRCA2-associated cancers, complementation group D1 fanconi anemia (MIM#605724) and Wilms tumor (MIM#194070). 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 1 heterozygote, 0 homozygotes). (SP) 0504 - Same amino acid change has been observed in placental mammals. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. While it has been identified as a germline variant in breast cancer patients (PMID: 18497862, 32885271), multifactorial-modelling suggests it’s non-pathogenicity (PMID: 16489001, 21990165). In addition, it has been classified as a VUS by expert panel Breast Cancer Information Core (BIC, ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1004 - This variant has moderate functional evidence supporting normal protein function. In vitro assays looking at cell survival and sensitivity to various DNA damaging agents demonstrated normal protein function (PMID: 33293522). (SB) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (4 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 869: S869X
PM5 criterion applied.
Functional Summary
The BRCA2 S869L variant has not been functionally characterized. Available evidence is inconclusive, with predictions suggesting it may be neutral, but lacking direct functional validation.
Database Previews
OncoKB
JAX-CKB
Click on previews to view full database entries. External databases may require institutional access.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.052
0.052
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
No
Additional Predictors
Benign:
CADD: 0.56polyphen_prediction: benignmetasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Null variant (nonsense, frameshift, splice site (donor/acceptor ±1,2), initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease." The evidence for this variant shows: it is a missense change (S869L), not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Strong: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no previously established pathogenic variant results in S869L. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "Strong: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS3 is: "Strong: Well-established in vitro or in vivo functional studies supportive of a damaging effect." The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong: The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls (p-value ≤0.05 and OR ≥4)." The evidence for this variant shows: no case-control data available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Moderate: Located in a mutational hotspot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: S869 is outside the BRCA2 PALB2‐binding domain (aa 10–40) and DNA‐binding domain (aa 2481–3186) with no known hotspot here. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent from controls in an outbred population, from gnomAD v2.1 and v3.1, average read depth ≥25." The evidence for this variant shows: present at MAF 0.000451% in gnomAD and 0.000947% in European (non-Finnish); not absent. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Supporting: Observed in trans with a pathogenic variant in patients with BRCA2-related Fanconi Anemia phenotype." The evidence for this variant shows: no Fanconi Anemia phenotype or trans observations. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Moderate: Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: missense variant with no length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Moderate: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen." The evidence for this variant shows: no record of a different pathogenic missense at residue S869. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting: Co-segregation with disease in multiple affected family members (LR ≥2.08:1)." The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Supporting: Missense variant in a gene with low rate of benign missense variation where missense is a common disease mechanism." The evidence for this variant shows: insufficient evidence on the gene’s benign missense rate. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting: Apply for missense variants inside a functional domain with BayesDel no-AF ≥0.30 or predicted splicing (SpliceAI ≥0.2)." The evidence for this variant shows: outside defined domains, BayesDel/REVEL scores low (REVEL 0.05), SpliceAI <0.2. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting/Strong: Phenotype specificity based on multifactorial likelihood data." The evidence for this variant shows: no multifactorial clinical data. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Supporting: Reputable source reports variant as pathogenic." The evidence for this variant shows: ClinVar submissions are VUS or LB, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand-alone: FAF >0.1% in gnomAD non-founder populations." The evidence for this variant shows: MAF 0.000947% <0.1%. Therefore, this criterion is not applied.
BS1
BS1 (Strong)
According to VCEP guidelines, the rule for BS1 is: "Strong: Filter allele frequency (FAF) is above 0.01% (FAF >0.0001) in gnomAD non-founder populations." The evidence for this variant shows: MAF in European (non-Finnish) is 0.000947 (0.0947%), above threshold. Therefore, this criterion is applied at Strong strength.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong/Moderate/Supporting: Observed in healthy adults lacking Fanconi Anemia features with point-based system." The evidence for this variant shows: no information on Fanconi Anemia phenotype in carriers. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Strong: Well-established functional studies show no damaging effect." The evidence for this variant shows: no functional assay data available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong/Moderate/Supporting: Lack of segregation in affected family members (LR thresholds)." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: "Strong: Silent or missense variants outside functional domains with no predicted splicing impact." The evidence for this variant shows: it is a missense variant but not a silent substitution; domain criteria not met. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Supporting: Observed in trans with a pathogenic variant for a dominant gene without disease." The evidence for this variant shows: no trans observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "Supporting: In-frame indels in repetitive regions." The evidence for this variant shows: this is a missense variant, not an indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting: Missense variants inside functional domains with BayesDel no-AF ≤0.18 and SpliceAI ≤0.1." The evidence for this variant shows: outside domains; computational scores low but domain criteria not met. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting/Strong: Presence of another pathogenic variant in a different breast–ovarian cancer gene without specific phenotype." The evidence for this variant shows: no such co-occurrence data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Supporting: Reputable source reports as benign." The evidence for this variant shows: ClinVar includes some Likely Benign calls but no consensus, and no other reputable source. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Supporting: Silent or intronic variants outside splice sites with no predicted impact, inside functional domains if BP4 met." The evidence for this variant shows: it is a missense variant, not silent/intronic. Therefore, this criterion is not applied.