BRCA1 c.3948C>T, p.Phe1316=
NM_007294.4:c.3948C>T
Likely Benign
This synonymous BRCA1 variant is absent from population databases (PM2), predicted to have no splicing impact (BP7), and is reported as likely benign by reputable sources (BP6). No pathogenic evidence is observed. The combination of two benign supporting criteria meets the threshold for Likely Benign.
ACMG/AMP Criteria Applied
PM2
BP6
BP7
Genetic Information
Gene & Transcript Details
Gene
BRCA1
Transcript
NM_007294.4
MANE Select
Total Exons
23
Strand
Reverse (−)
Reference Sequence
NC_000017.10
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_007294.2 | Alternative | 23 exons | Reverse |
| NM_007294.3 | RefSeq Select | 23 exons | Reverse |
Variant Details
HGVS Notation
NM_007294.4:c.3948C>T
Protein Change
F1316=
Location
Exon 10
(Exon 10 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_007294.4
Genome Browser
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HGVS InputNM_007294:c.3948C>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 3 submitter reviews in ClinVar
Submitter Breakdown
3 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 (3 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: 0.49
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 a gene where loss of function is a known mechanism. This variant is a synonymous change (F1316=) and does not introduce a null effect. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS1 applies when a variant leads to the same amino acid change as a known pathogenic variant. This variant is synonymous and does not change the amino acid. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies for confirmed de novo occurrences in a patient with the disease and no family history. No de novo evidence or parental testing data are available. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 requires well-established functional studies demonstrating a damaging effect. No functional assay data are available for this variant. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 applies when the variant is significantly enriched in affected individuals versus controls (p≤0.05, OR≥4). No case–control or cohort enrichment data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to variants located in a mutational hotspot or well-established functional domain without benign variation. F1316= is outside the defined clinically important domains (RING 2–101, coiled-coil 1391–1424, BRCT 1650–1857). Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, "Absent from controls in an outbred population, from gnomAD v2.1 (non-cancer, exome only subset) and gnomAD v3.1 (non-cancer). Region around the variant must have an average read depth ≥25." The variant is not present in gnomAD or other population databases. Therefore, PM2 is applied at Supporting strength because it is absent from population controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies for biallelic variants in patients with BRCA1/2-related Fanconi anemia. No phenotype or trans‐occurrence 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 or in‐frame indels. This is a synonymous change with no protein length effect. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM5 applies when a novel missense change occurs at an amino acid residue where a different pathogenic missense change has been seen. This variant is synonymous. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies for assumed de novo occurrences without parental confirmation. No de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires segregation data in multiple affected family members. No family segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies for missense variants in a gene with a low rate of benign missense variation. This variant is synonymous. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 applies for computational evidence predicting a deleterious effect in missense or splicing. In silico tools predict no impact on splicing or protein. However, PP3 is for pathogenic predictions; here predictions are benign, so PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies when patient phenotype is highly specific for a single gene. No clinical phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source reports a variant as pathogenic without evidence. No such report exists. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies when allele frequency >0.1% in gnomAD non-cancer populations. The variant is absent. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies when allele frequency is >0.01% but ≤0.1%. The variant is absent. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies in absence of features of recessive disease (Fanconi anemia). No such cohort data are available. 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 assay data are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies to lack of segregation in families. No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 applies to missense or in-frame indels outside functional domains with no splicing predicted. This is synonymous, not missense. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when variant co-occurs with a pathogenic variant with no additional phenotype. 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. Not applicable to a single nucleotide synonymous change. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, BP4 applies to benign computational evidence for missense or in-frame variants inside functional domains or intronic variants outside splice sites. This is a silent exonic variant outside those scenarios. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies to combined clinical evidence against pathogenicity. No such clinical data are provided. Therefore, BP5 is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." ClinVar lists this variant as Likely benign by three clinical laboratories. Therefore, BP6 is applied at Supporting strength because of the reputable source assertion.
BP7
BP7 (Supporting)
According to standard ACMG guidelines, BP7 applies to a synonymous variant for which splicing prediction algorithms predict no impact. SpliceAI predicts no splicing impact (maximum score 0.05). Therefore, BP7 is applied at Supporting strength because there is no predicted splicing alteration.