BRCA2 c.2090A>C, p.Lys697Thr
NM_000059.4:c.2090A>C
Variant of Uncertain Significance (VUS)
K697T in BRCA2 remains a VUS: PM5 (Moderate) and PM2 (Supporting) support pathogenicity, while BP1 (Strong) supports a benign interpretation. Conflicting evidence and lack of additional data prevent reclassification.
ACMG/AMP Criteria Applied
PM2
PM5
BP1
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.2090A>C
Protein Change
K697T
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 697: K697E, K697N
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.2090A>C
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
Unknown
Publications (0)
No publication details.
Clinical Statement
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 697: K697E, K697N
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.292
0.292
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: 2.40metasvm: 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, PVS1 applies to null variants in a gene where loss of function is a known mechanism. The evidence for NM_000059.4:c.2090A>C shows it is a missense variant, not a null variant. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when a variant causes the same amino acid change as a previously established pathogenic variant. There is no report of a K697T change previously classified as pathogenic. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence with parental testing. No parental data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to VCEP guidelines, PS3 requires well-established functional studies showing a damaging effect. No functional assays have been performed for K697T. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires case-control data showing significant enrichment in affected individuals. No such data exist for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to variants in clinically important functional domains (BRCA2 aa 10–40 or 2481–3186). K697T lies outside these domains. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2_Supporting: "Absent from controls in an outbred population, from gnomAD v2.1 and v3.1." The evidence shows this variant is not found in gnomAD. Therefore, PM2 is applied at Supporting strength because the variant is absent from control populations per VCEP PM2 criteria.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 requires evidence of co-occurrence in trans with a pathogenic variant in a Fanconi anemia phenotype. No such data are available. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels). This is a missense variant with no length change. Therefore, PM4 is not applied.
PM5
PM5 (Moderate)
According to standard ACMG guidelines, PM5_Moderate: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen." The evidence shows a pathogenic missense at K697 has been reported. Therefore, PM5 is applied at Moderate strength because K697 is a residue with a known pathogenic missense change.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo variants without parental confirmation. No de novo assumption is documented. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires co-segregation evidence in multiple affected family members. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation and where missense is a common mechanism. BRCA2 has many benign missense variants and no specific PP2 guidance. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 applies when computational evidence predicts a deleterious effect inside a functional domain or predicted splicing impact (SpliceAI ≥0.2). In silico tools predict no impact and SpliceAI = 0. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 requires phenotype specificity and multifactorial likelihood data. No clinical phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 requires a reputable source classification of the variant as pathogenic. This variant is not in ClinVar or equivalent. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies to variants with allele frequency >0.1% in gnomAD. This variant is absent. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies to variants with filter allele frequency >0.01% in gnomAD. This variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 requires observation in healthy adults. No such observations are reported. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 requires well-established functional studies showing no damaging effect. No functional data exist. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires lack of segregation in affected family members. No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Strong) Strength Modified
According to VCEP guidelines, BP1_Strong: "Missense variants outside clinically important functional domains AND no splicing predicted (SpliceAI ≤0.1)." K697T lies outside BRCA2 domains and SpliceAI = 0. Therefore, BP1 is applied at Strong strength because it is a missense change outside defined functional domains with no predicted splicing impact.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 requires co-occurrence in cis with a pathogenic variant. No co-occurrence data are available. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a missense variant. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 applies to variants inside functional domains with no predicted impact. K697T is outside domains. Therefore, BP4 is not applied under VCEP specifications.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 requires multifactorial clinical data on co-observation with other pathogenic variants. No such data exist. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 requires a reputable source classification of the variant as benign. This variant is not in such sources. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to silent or intronic variants outside splice sites with no impact. This is a missense variant. Therefore, BP7 is not applied.