BRCA2 c.5722C>T, p.Leu1908=
NM_000059.4:c.5722C>T
Likely Benign
Three supporting benign criteria (PM2, BP6, BP7) with absence of any pathogenic evidence support a Likely Benign classification for the BRCA2 c.5722C>T (L1908=) variant.
ACMG/AMP Criteria Applied
PM2
BP6
BP7
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.5722C>T
Protein Change
L1908=
Location
Exon 11
(Exon 11 of 27)
5'Exon Structure (27 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000059.4
Genome Browser
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HGVS InputNM_000059:c.5722C>T
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
Likely Benign
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.79
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 ...). Apply at appropriate strength according to PVS1 flowchart." The evidence for this variant shows: c.5722C>T is a synonymous (L1908=) change, not predicted to cause loss of function. Therefore, this criterion is not applied because the variant is not a null variant as defined by the rule.
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." The evidence for this variant shows: it is a synonymous change (no amino acid change). Therefore, this criterion is not applied because it does not alter the protein sequence.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no information on de novo status. Therefore, this criterion is not applied due to lack of de novo data.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "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 because functional impact has not been assessed.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong: prevalence of the variant in affected individuals is significantly increased compared to controls (p≤0.05, OR≥4)." The evidence for this variant shows: no case-control or prevalence data. Therefore, this criterion is not applied due to absence of epidemiological evidence.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Moderate: located in a mutational hot spot or well‐established functional domain without benign variation." The evidence for this variant shows: c.5722C>T is a synonymous change outside defined functional domains. Therefore, this criterion is not applied because it does not lie in a critical domain.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting: Absent from controls in gnomAD v2.1 and v3.1 (non‐cancer)." The evidence for this variant shows: it is not found in gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is absent from large population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Apply for patients with phenotype consistent with BRCA2‐related Fanconi Anemia and co‐occurring variants." The evidence for this variant shows: no Fanconi Anemia phenotype or allelic data. Therefore, this criterion is not applied due to lack of phenotype and allelic information.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in‐frame insertions/deletions." The evidence for this variant shows: it is a synonymous change without length alteration. Therefore, this criterion is not applied because protein length is unchanged.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Moderate: different pathogenic stop‐gain variant in the same exon." The evidence for this variant shows: it is synonymous, not introducing a stop codon. Therefore, this criterion is not applied as it does not create a PTC.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." The evidence for this variant shows: no de novo information. 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 affected family members (LR≥2.08)." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied due to lack of segregation information.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism." The evidence for this variant shows: it is synonymous. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting: computational evidence for impact (BayesDel ≥0.30 or SpliceAI ≥0.2)." The evidence for this variant shows: SpliceAI predicts no splicing impact (score 0.00). Therefore, this criterion is not applied because computational tools do not predict a deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Supporting: patient’s phenotype or family history is highly specific for a gene." The evidence for this variant shows: no clinical phenotype data. Therefore, this criterion is not applied due to lack of phenotype-specific information.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic or likely pathogenic without available evidence." The evidence for this variant shows: ClinVar reports likely benign. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: allele frequency >0.1% in gnomAD." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: allele frequency >0.01% and ≤0.1% in gnomAD." The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong: absence of recessive phenotype in ≥4 individuals." The evidence for this variant shows: no Fanconi Anemia phenotype data. 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 assays performed. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong: lack of segregation in affected members (LR≤0.05)." 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 variant outside functional domain with no splicing effect." The evidence for this variant shows: silent outside domain but BP1 applies only to missense/in‐frame. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorder." The evidence for this variant shows: no co‐occurrence data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in repetitive regions without known function." The evidence for this variant shows: it is 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: computational evidence shows no impact for missense/in‐frame variants inside domain or intronic outside splice sites." The evidence for this variant shows: it is synonymous outside domain. Therefore, this criterion is not applied under the VCEP definition.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Supporting: variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no co‐observation with other pathogenic variants. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Supporting: reputable source reports variant as benign without available evidence." The evidence for this variant shows: ClinVar lists it as Likely Benign. Therefore, this criterion is applied at Supporting strength because a reputable database reports it as benign without detailed evidence.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "Supporting: synonymous variant with no predicted splicing impact." The evidence for this variant shows: SpliceAI predicts no impact on splicing. Therefore, this criterion is applied at Supporting strength because it is a silent change with no splicing effect.