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NM_007294.4:c.3245C>T
p.Ala1082Val · BRCA1
ClinGen ENIGMA BRCA1 and BRCA2 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for BRCA1 Version 1.2 · v1.2
0%
complete
Final classification
VUS
BP1
BRCA1
c.3245C>T
p.Ala1082Val
missense · exon 10
Gene context NCBI Gene ↗ OncoKB ↗

BRCA1 encodes a large nuclear protein that helps maintain genomic stability by coordinating the repair of DNA double-strand breaks through homologous recombination, and it also regulates transcription and the cell cycle. It acts as a tumor suppressor, working with proteins such as RAD51, BRCA2, BARD1, and PALB2 to preserve genome integrity. Inherited alterations in BRCA1 cause hereditary breast and ovarian cancer syndrome, with elevated risks of breast, ovarian, prostate, and pancreatic cancers, and biallelic loss underlies a rare form of Fanconi anemia. Because BRCA1-driven tumors rely on impaired DNA repair, they are treatable with PARP inhibitors.

This variant

NM_007294.4:c.3245C>T changes BRCA1 p.Ala1082Val in a protein that supports homologous-recombination DNA repair and tumor-suppressor function in hereditary breast and ovarian cancer syndrome.

Transcript
NM_007294.4
HGVS · transcript:coding
NM_007294.4:c.3245C>T
GRCh38
chr17:43092286 G>A
GRCh37
chr17:41244303 G>A
VUS: BP1 (strong) is the only applied criterion and does not meet ENIGMA's likely-benign combination rule without additional benign evidence.
Classification rationale
BP1 VUS
BRCA1 c.3245C>T missense · exon 10

VUS: BP1_Strong is met because Ala1082 lies outside the specified BRCA1 domains and SpliceAI is 0.008. VUS: No additional benign or pathogenic criterion combination is met under ENIGMA Table 3.

BP1 → VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
Gene diagram · NM_007294.4 · variants mapped to exon structure
BRCA1 NM_007294.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 15 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength Supporting Moderate Strong Very strong
BP1 strong Benign
Met at Strong: Ala1082 is outside ENIGMA domains and SpliceAI maximum delta is 0.008, below the ≤0.1 no-splicing threshold.
Specifications V1.2 Table 1, BP1_Strong: applies to silent, missense, or in-frame insertion/deletion/delins variants outside a potentially clinically important functional domain with SpliceAI ≤0.1; missense prediction is not applicable.Appendix J/Table 16 lists the applicable BRCA1 domains as RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857; p.Ala1082Val is outside these ranges.SpliceAI case result: maximum delta score 0.008 (DS_AG 0.008, DS_AL 0.000, DS_DG 0.000, DS_DL 0.001).
vcep_specifications_v1_2_2024_11_18 ↗vcep_appendices_v1_2_2024_11_18 ↗cspec ↗spliceai ↗
Assessed · not applied · 1 not met · 14 not assessed
Pathogenic
PS1 Not assessed: SpliceAI is 0.008, but no qualifying pathogenic or likely pathogenic alternate nucleotide change producing p.Ala1082Val was identified.
PS3 Not assessed: no variant-specific calibrated protein or combined mRNA/protein assay result or pre-assigned PS3 code was found for c.3245C>T.
PS4 Not assessed: no variant-specific case-control p-value, OR, or confidence interval is available to evaluate p-value ≤0.05 and OR ≥4 with a lower CI excluding 2.0.
PM2 Not assessed: the variant is absent from both specified non-cancer gnomAD datasets, but required average read depth (>=25) is not reported.
PM3 Not assessed: no documented co-occurring BRCA1 pathogenic variant, phase information, or qualifying Fanconi Anemia phenotype is available.
PP1 Not assessed: no quantitative co-segregation likelihood ratio or documented informative affected-family meioses is available for this variant.
PP3 Not met: SpliceAI maximum delta 0.008 is below the VCEP PP3 splice threshold of ≥0.2, and the variant is outside the domain required for the protein-impact path.
PP4 Not assessed: no combined multifactorial clinical LR is available for comparison with the PP4 supporting threshold of LR ≥2.08:1.
Benign
BA1 Not assessed: gnomAD non-cancer records are absent, but the required BA1 FAF threshold (>0.001) and read-depth quality gate are not reported.
BS1 Not assessed: gnomAD non-cancer records are absent, but the required BS1 FAF thresholds (>0.00002) and read-depth quality gate are not reported.
BS2 Not assessed: no qualifying healthy-adult, zygosity, Fanconi Anemia, follow-up, or BS2 point data are available.
BS3 Not assessed: no variant-specific calibrated benign protein or combined mRNA/protein assay result or pre-assigned BS3 code was found for c.3245C>T.
BS4 Not assessed: no quantitative non-segregation likelihood ratio or documented affected-family discordance is available for this variant.
BP5 Not assessed: no combined clinical LR is available for the governing BP5 comparison LR ≤0.48, so the benign-supporting threshold cannot be tested.
BP7 Not assessed: The variant is eligible for BP7_Strong (RNA), but no qualifying mRNA-only assay result is available; SpliceAI 0.008 alone is insufficient.
N/A · 12 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP4 · BP6
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 441288)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.481. BayesDel score = -0.0316675.
SpliceAI ↗
Functional / OncoKB screenshot
Functional Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. BRCA1, a tumor suppressor involved in the DNA damage response, is mutated in various cancer types.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
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.
COSMIC ↗ Hotspots ↗
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 7 PMIDs not cited in assessment
25230021 ↗ Ovarian cancer cell line panel (OCCP): clinical importance of in vitro morphological subtypes. CLINVAR
31911673 ↗ Systematic misclassification of missense variants in BRCA1 and BRCA2 "coldspots". CLINVAR
17392385 ↗ American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CLINVAR
23188549 ↗ NSGC practice guideline: risk assessment and genetic counseling for hereditary breast and ovarian cancer. CLINVAR
24366376 ↗ Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. CLINVAR
24432435 ↗ PMID 24432435 CLINVAR
24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR