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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

This BRCA1 missense change affects a tumor-suppressor protein involved in homologous-recombination DNA repair and is relevant to inherited breast and ovarian cancer susceptibility.

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 ENIGMA Table 3 requires multiple benign evidence types for a single Strong benign criterion to support Likely Benign.
Classification rationale
BP1 VUS
BRCA1 c.3245C>T missense · exon 10

BP1 Strong met: Ala1082 is outside approved BRCA1 functional domains and SpliceAI is 0.008. VUS: BP1 Strong alone lacks the multiple benign evidence types required for Likely Benign 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 all approved BRCA1 domains and SpliceAI max delta 0.008 is below the ENIGMA <=0.1 threshold.
ENIGMA BP1_Strong applies to missense variants outside a potentially clinically important functional domain with no predicted splicing, using SpliceAI <=0.1.Ala1082 is outside the ENIGMA BRCA1 domains RING aa 2-101, coiled-coil aa 1391-1424, and BRCT repeats aa 1650-1857.The case SpliceAI max delta is 0.008, satisfying the ENIGMA no-predicted-splicing threshold.
cspec ↗spliceai ↗
Assessed · not applied · 4 not met · 11 not assessed
Pathogenic
PS1 Not assessed: SpliceAI max delta is 0.008, but no previously pathogenic p.Ala1082 substitution was identified for the required same-amino-acid comparison.
PS3 Not assessed: no variant-level PS3 recommendation or functional assay result was found for c.3245C>T/p.Ala1082Val in the governing VCEP sources.
PS4 Not assessed: no variant-specific case-control odds ratio, p-value, or confidence interval was available to evaluate the ENIGMA PS4 thresholds.
PM2 Not assessed: the variant is absent from both specified non-cancer gnomAD datasets, but the required regional average read depth of at least 25 is not reported.
PM3 Not assessed: no documented same-gene pathogenic/likely pathogenic variant in trans or Fanconi-anemia phenotype is available for point assignment.
PP1 Not assessed: no variant-specific segregation LR or affected-relative data were available, and the governing multifactorial table contained no c.3245C>T entry.
PP3 Not met: REVEL 0.481 is below the >=0.644 supporting PP3 threshold for missense variants.
PP4 Not assessed: no combined multifactorial likelihood ratio was available for comparison with the PP4 supporting threshold of >=2.08:1.
Benign
BA1 Not met: the variant is absent from the specified non-cancer gnomAD datasets, so its filter allele frequency does not exceed the 0.001 BA1 threshold.
BS1 Not met: absence from the specified non-cancer gnomAD datasets provides no filter allele frequency above 0.00002, the minimum BS1 threshold.
BS2 Not assessed: no qualifying proband-level phase, homozygote, age/follow-up, cancer-status, or Fanconi Anemia data are available for the BS2 point system.
BS3 Not assessed: no variant-level BS3 recommendation or functional assay result was found for c.3245C>T/p.Ala1082Val in the governing VCEP sources.
BS4 Not assessed: no variant-specific non-segregation LR or family genotype data were available, and the governing multifactorial table contained no c.3245C>T entry.
BP4 Not met: REVEL 0.481 is above the <=0.29 supporting BP4 threshold for missense variants.
BP5 Not assessed: no combined multifactorial likelihood ratio was available to test against the BP5 supporting inequality LR <=0.48:1.
N/A · 12 PVS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · PP5 · BP2 · BP3 · BP6 · BP7
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
23918944 ↗ Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. CLINVAR
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
12692171 ↗ American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. CLINVAR
19305347 ↗ ACOG Practice Bulletin No. 103: Hereditary breast and ovarian cancer syndrome. CLINVAR
27854360 ↗ Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. CLINVAR
31429903 ↗ Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement. CLINVAR