BRCA1 c.3938A>G, p.Gln1313Arg
NM_007294.4:c.3938A>G
Variant of Uncertain Significance (VUS)
The variant NM_007294.4:c.3938A>G (p.Q1313R) is a missense change absent from controls (PM2_supporting) but observed at a frequency above the benign threshold (BS1_strong), with no functional or segregation evidence of pathogenicity, and with benign computational and positional evidence (BP1_strong, BP4_supporting). These data support a Likely Benign classification.
ACMG/AMP Criteria Applied
PM2
BS1
BP1
BP4
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.3938A>G
Protein Change
Q1313R
Location
Exon 10
(Exon 10 of 23)
5'Exon Structure (23 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1313 in gene BRCA1
Variant interpretation based on transcript NM_007294.4
Genome Browser
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HGVS InputNM_007294:c.3938A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
African/African American
0.00615%
Rare
Global: 0.000398%
African/African American: 0.00615%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251228Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251228 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.00615%, 1/16256 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
1 publications
Uncertain Significance (VUS)
Based on 5 submitter reviews in ClinVar
Submitter Breakdown
5 VUS
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (5 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
No evidence of other pathogenic variants at position 1313 in gene BRCA1
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.536
0.536
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: 2.92metasvm: 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 PVS1 rule applies to null variants (nonsense, frameshift, splice site ±1,2) in a gene where loss of function is a known mechanism of disease. The evidence for NM_007294.4:c.3938A>G shows it is a missense variant (Q1313R), not a null variant. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when a variant results in the same amino acid change as a previously established pathogenic variant. The evidence for NM_007294.4:c.3938A>G shows no known pathogenic variant causing Q1313R. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies for de novo occurrences with confirmed maternity and paternity. No parental testing or de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 requires well-established functional studies supportive of a damaging effect. No functional assay data exist for Q1313R. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 applies when the prevalence of the variant in affected individuals is significantly increased compared to controls (OR≥4, p≤0.05). No case-control or affected-individual data are available for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to missense variants located in a clinically important functional domain (RING 2–101; coiled-coil 1391–1424; BRCT 1650–1857). The evidence for Q1313R shows the residue (1313) is 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 (non-cancer) and gnomAD v3.1 (non-cancer)." The evidence for NM_007294.4:c.3938A>G shows a gnomAD MAF of 0.000398%, which is extremely rare. Therefore, PM2 is applied at Supporting strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies for biallelic variants in patients with a Fanconi Anemia phenotype. No such phenotype or co-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 from in-frame insertions/deletions. NM_007294.4:c.3938A>G is a missense change, not an in-frame indel. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies to new missense changes at residues where other pathogenic missense changes have been observed. No pathogenic variants at codon 1313 are reported. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo cases without confirmation. No de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies for co-segregation in multiple affected family members with quantitative evidence. No 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 low benign missense variation where missense is a known mechanism. BRCA1 has many benign and uncertain missense variants and this position is not a hotspot; PP2 is therefore not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 applies for missense variants inside clinically important domains with BayesDel no-AF ≥0.28 or SpliceAI ≥0.2. Q1313R is outside defined domains and SpliceAI=0.09 (<0.2), and in silico predictors are mixed. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 applies for a patient’s phenotype highly specific for a single gene disorder. 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 classifies the variant as pathogenic. ClinVar lists this variant as VUS across laboratories. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies when allele frequency exceeds 0.1% in gnomAD non-cancer. The observed MAF is 0.000398% (<0.1%). Therefore, BA1 is not applied.
BS1
BS1 (Strong)
According to VCEP guidelines, "BS1: Strong Filter allele frequency (FAF) is above 0.01% (FAF > 0.0001) in gnomAD non-cancer." The evidence shows MAF=0.000398 (0.0398%), which is >0.01%. Therefore, BS1 is applied at Strong strength.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies for healthy adult individuals lacking disease features. No healthy adult genotype–phenotype data are provided. 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 such assays exist for Q1313R. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies for 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: Apply for missense variants outside a clinically important functional domain AND no splicing predicted (SpliceAI ≤0.1)." Q1313R lies outside defined domains and SpliceAI=0.09. Therefore, BP1 is applied at Strong strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when observed in trans with a pathogenic variant for a dominant disorder. No such observations are reported. 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. NM_007294.4:c.3938A>G is not an indel. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, "BP4: Supporting — no predicted impact via protein change or splicing (BayesDel no-AF ≤0.15 AND SpliceAI ≤0.1)." SpliceAI=0.09 predicts no splicing impact and computational tools are predominantly benign. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies when a variant is found alongside a pathogenic variant in a gene without unique phenotype. No co-occurrence data exist. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source classifies a variant as benign. No such classification exists. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous variants with no predicted splicing impact. Q1313R is missense, not silent. Therefore, BP7 is not applied.