c.507G>A is a silent (synonymous) substitution in BRCA1 exon 7 producing p.Gln169= (NP_009225.1:p.(Q169=)). BP1_Strong is met: the variant is a silent substitution at residue 169, which is outside all three BRCA1 clinically important functional domains (RING aa2-101, coiled-coil aa1391-1424, BRCT repeats aa1650-1857), and SpliceAI predicts no splicing impact (max delta 0.01).1 The variant is present at very low frequency in gnomAD population databases (v2.1: 3/282870 alleles; v4.1: 28/1613772 alleles) but does not meet BS1 or BA1 thresholds.2 PVS1, PS1, PS5, PM5, and BP4 are not applicable due to the silent nature of the variant. PP3 is not met (SpliceAI 0.01 < 0.2). PM2 is not met (variant is present in gnomAD).3 PS3, BS3, and BP7 remain not assessed pending verification of a reported minigene splicing assay (Fraile-Bethencourt et al. 2017) that found no splicing aberration. Confirmation of this finding would support BS3 and BP7. PP4 and BP5 are not assessed because the variant is not represented in the Li et al. 2020 (PMID:31853058) clinical-history likelihood ratio table or the Parsons et al. 2019 multifactorial dataset.4 ClinVar reports an ENIGMA expert panel classification of Likely benign (ClinVar ID 185706, review status: reviewed by expert panel). The ENIGMA classification likely incorporates the minigene splicing evidence and/or additional clinical data not captured in the available VCEP spreadsheets.5 Under strict ENIGMA Table 3 combining rules, BP1_Strong alone is insufficient to reach Likely Benign without at least one additional supporting benign criterion of a different evidence type. The available data therefore place this variant between Likely Benign (per ENIGMA expert panel classification) and VUS (per strict criteria-based adjudication without verified BS3/BP7).6
BRCA1
Final classification
Likely Benign
BRCA1 c.507G>A · p.Gln169=
BRCA1
c.507G>A is a silent (synonymous) substitution in BRCA1 exon 7 producing p.Gln169= (NP_009225.1:p.(Q169=)).
ENIGMA Table 3: 1 Strong (Benign) + 1 Supporting (Benign) = Likely Benign. Point score: -5 (range -6 to -2).
Classification rationale
BP1BP6
Likely Benign
BRCA1 c.507G>A
BP1 + BP6
→
Likely Benign
4
vcep_pmid_31853058_brca1_clinical_history_lrvcep_humu_40_1557_s001
Gene diagram
· NM_007294.4 · variants mapped to exon structure
BRCA1
NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
Population frequency
Overall AF
28 / 1,613,772
0.0017%
Highest · African/African American
0.004%
Homozygotes
0
grpmax FAF
0.0015%
Allele frequency by ancestry — gnomAD v4.1
observed in 2 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| African/African American | 3 / 75,036 | 0.004% | 0 |
| European (non-Finnish) | 25 / 1,179,678 | 0.0021% | 0 |
| Admixed American | 0 / 60,012 | — | — |
| European (Finnish) | 0 / 64,024 | — | — |
| Amish | 0 / 912 | — | — |
| East Asian | 0 / 44,880 | — | — |
| Middle Eastern | 0 / 6,060 | — | — |
| South Asian | 0 / 91,080 | — | — |
| Ashkenazi Jewish | 0 / 29,600 | — | — |
“
This variant is present in gnomAD v4.1 (AF= 1.73507e-05; MAF= 0.00174%, 28/1613772 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 3.99808e-05; MAF= 0.00400%, 3/75036 alleles, homozygotes = 0); grpmax FAF= 1.455e-05.
Overall AF
3 / 282,870
0.0011%
Highest · African/African American
0.008%
Homozygotes
0
Allele frequency by ancestry — gnomAD v2.1
observed in 2 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| African/African American | 2 / 24,968 | 0.008% | 0 |
| European (non-Finnish) | 1 / 129,174 | 0.00077% | 0 |
| Admixed American | 0 / 35,440 | — | — |
| Ashkenazi Jewish | 0 / 10,370 | — | — |
| East Asian | 0 / 19,954 | — | — |
| European (Finnish) | 0 / 25,124 | — | — |
| Remaining individuals | 0 / 7,224 | — | — |
| South Asian | 0 / 30,616 | — | — |
“
This variant is present in gnomAD v2.1 (AF= 1.06056e-05; MAF= 0.00106%, 3/282870 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.01025e-05; MAF= 0.00801%, 2/24968 alleles, homozygotes = 0).
“
This variant is absent from gnomAD-Canada.
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 185706)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.014.
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · 23 PMIDs triaged · 8 high-priority
23papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
23918944 ↗
splicing rna
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers. Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familia
BP7PP3PP5PS4PVS1
25741868 ↗
functional
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic
BS3PS3PS4
26467025 ↗
functional
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies
BS3PS3PS4
12692171 ↗
case observation
American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
As the leading organization representing cancer specialists involved in patient care and clinical research, the American Society of Clinical Oncology (ASCO) reaffirms its commitment to integrating cancer risk assessment and management, including molecular analysis of cancer predisposition genes, into the practice of oncology and preventive medicine. The primary goal of this effort is to foster exp
PP5PS4
15604628 ↗
case observation
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in
PP5PS4
17392385 ↗
case observation
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
New evidence on breast Magnetic Resonance Imaging (MRI) screening has become available since the American Cancer Society (ACS) last issued guidelines for the early detection of breast cancer in 2003. A guideline panel has reviewed this evidence and developed new recommendations for women at different defined levels of risk. Screening MRI is recommended for women with an approximately 20-25% or gre
PP5PS4
17508274 ↗
case observation
Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
These cancer genetic counseling recommendations describe the medical, psychosocial and ethical implications of identifying at-risk individuals for hereditary breast and ovarian cancer (HBOC) through cancer risk assessment, with or without genetic susceptibility testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors' Familial Cancer
PP5PS4
18163131 ↗
case observation
The emerging landscape of breast cancer susceptibility.
The genetic basis of inherited predisposition to breast cancer has been assiduously investigated for the past two decades and has been the subject of several recent discoveries. Three reasonably well-defined classes of breast cancer susceptibility alleles with different levels of risk and prevalence in the population have become apparent: rare high-penetrance alleles, rare moderate-penetrance alle
PP5PS4
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PS3PS4
Sources & reference links