Final classification

Likely Benign

BS1BP1BP6

BRCA2

c.1167G>A

p.Pro389=

synonymous · exon 10

Gene context NCBI Gene ↗ OncoKB ↗

BRCA2 encodes a DNA repair protein that maintains genome stability by repairing double-strand breaks through homologous recombination and by protecting DNA replication forks. It acts as a tumor suppressor, and inherited loss-of-function changes cause hereditary breast and ovarian cancer syndrome, with elevated lifetime risks of breast, ovarian, prostate, and pancreatic cancers; biallelic changes cause Fanconi anemia complementation group D1. Reduced or altered BRCA2 activity is implicated in multiple tumor types, and PARP inhibitors are an approved treatment for BRCA2-associated ovarian and breast cancers.

This variant

BRCA2 encodes a homologous-recombination DNA-repair tumor suppressor, and inherited loss of function causes hereditary breast and ovarian cancer syndrome and related cancer risks.

Transcript

NM_000059.4

HGVS · transcript:coding

NM_000059.4:c.1167G>A

GRCh38

chr13:32332645 G>A

GRCh37

chr13:32906782 G>A

Likely Benign: BS1 Supporting, BP1 Strong benign, and BP6 Supporting benign total -6 under the ENIGMA BRCA2 point system.

Classification rationale

BS1BP1BP6 Likely Benign

BRCA2 c.1167G>A synonymous · exon 10

BS1 Supporting: gnomAD v3.1 non-cancer genome FAF 6.803e-05 falls within ENIGMA's benign-supporting frequency interval. BP1 Strong benign: synonymous residue 389 is outside the approved BRCA2 functional domains and SpliceAI max delta is 0.001. BP6 Supporting benign: the exact variant has a three-star ENIGMA expert-panel Likely benign classification in ClinVar.

BS1 + BP1 + BP6 → Likely Benign

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_000059.4 · variants mapped to exon structure

BRCA2 NM_000059.4

Fetching transcript structure from UCSC…

Applied criteria · 3 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 · 3

Strength Supporting Moderate Strong Very strong

BS1 supporting Benign

Met at Supporting: gnomAD v3.1 non-cancer genome grpmax FAF 6.803e-05 falls between the ENIGMA BS1 Supporting limits >2e-05 and <=1e-04.

ENIGMA specifies BS1 Supporting for FAF >0.00002 and <=0.0001 in non-founder gnomAD populations, with exome and genome data assessed separately.The gnomAD v3.1 non-cancer genome record reports grpmax FAF 6.803e-05, meeting the ENIGMA BS1 Supporting interval.The gnomAD v2.1 non-cancer exome FAF is 1.969e-05, below the BS1 Supporting lower bound; the qualifying evidence is the v3.1 non-cancer genome value.

cspec ↗gnomad_v2 ↗

BP1 strong review Benign

Met, Strong: synonymous residue 389 is outside BRCA2 domains aa 10-40 and 2481-3186, with SpliceAI max delta 0.001 versus the ≤0.1 threshold.

ENIGMA BRCA2 v1.2 specifies BP1_Strong for silent substitutions outside a potentially clinically important functional domain with SpliceAI ≤0.1.Residue 389 is outside the VCEP-approved BRCA2 PALB2-binding domain aa 10-40 and DNA-binding domain aa 2481-3186.SpliceAI max delta is 0.001, below the governing VCEP threshold of 0.1.

cspec ↗spliceai ↗

BP6 supporting Benign

Met, Supporting: the exact variant has a ClinVar 3-star ENIGMA expert-panel classification of Likely benign.

ClinVar identifies the exact transcript variant NM_000059.4(BRCA2):c.1167G>A (p.Pro389=), variation 184355, with review status reviewed by expert panel and classification Likely benign by ENIGMA.BP6 was applied only from the exact-variant expert-panel classification; ordinary laboratory submissions and aggregate ClinVar labels were not used.ClinVar expert panel classification

clinvar ↗

Assessed · not applied · 6 not met · 9 not assessed

Pathogenic

PS3 Not assessed: no calibrated damaging functional assay was reported for c.1167G>A (p.Pro389=), and SpliceAI max delta 0.001 is not PS3 evidence.

PS4 Not assessed: 6/793 cases versus 0/167 controls was reported, but the required PS4 p-value, OR >=4, and lower confidence limit excluding 2.0 are unavailable.

PM2 Not met: the variant is present in gnomAD v2.1 non-cancer exomes at AF 3.81942e-05 and gnomAD v3.1 non-cancer genomes at AF 6.75941e-05.

PM3 Not assessed: no documented Fanconi anemia phenotype, same-gene pathogenic variant, or phase information is available to satisfy the ENIGMA PM3 rule.

PP1 Not assessed: no quantitative co-segregation LR or affected-relative meioses are available to reach the ENIGMA PP1 threshold of LR >=2.08.

PP3 Not met: SpliceAI maximum delta 0.001 is below the ENIGMA PP3 threshold of 0.2 for silent variants.

PP4 Not assessed: no exact BRCA2 c.1167G>A combined clinical-history LR was found for comparison with the PP4 threshold >=2.08.

PP5 Not met: the exact-variant ClinVar expert panel classified c.1167G>A as Likely benign, not Pathogenic or Likely pathogenic.

Benign

BA1 Not met: maximum applicable non-cancer FAF is 6.803e-05, below the ENIGMA BA1 threshold of >0.001.

BS2 Not assessed: gnomAD records show 0 homozygotes, but ENIGMA excludes frequency-dataset homozygotes and provides no qualifying phenotyped individual-level BS2 points.

BS3 Not assessed: no calibrated benign functional assay was reported for c.1167G>A (p.Pro389=), and SpliceAI max delta 0.001 is not BS3 evidence.

BS4 Not assessed: no quantitative non-segregation LR or affected-relative genotype data are available to reach the ENIGMA BS4 threshold of LR <=0.48.

BP4 Not met: SpliceAI maximum delta 0.001 is below 0.1, but ENIGMA BP4 requires a silent variant inside a clinically important BRCA2 domain.

BP5 Not assessed: no exact BRCA2 c.1167G>A clinical-history LR was available for the BP5 comparison LR <=0.48.

BP7 Not met: Pro389 lies outside ENIGMA's qualifying domains, and no mRNA-only assay supports the alternative BP7_Strong route.

N/A · 10 PVS1 · PS1 · PS2 · PM1 · PM4 · PM5 · PM6 · PP2 · BP2 · BP3

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

The gnomAD v4.1 query FAILED for this variant, so its frequency in v4.1 is UNKNOWN. This is missing data, NOT evidence of absence or rarity, and must not support PM2 or any frequency-based criterion.

v2.1

The gnomAD v2.1 query FAILED for this variant, so its frequency in v2.1 is UNKNOWN. This is missing data, NOT evidence of absence or rarity, and must not support PM2 or any frequency-based criterion.

🇨🇦 CA

Not available in 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

This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Likely benign by Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) (expert panel). (ClinVarID = 184355)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 8 further PMIDs triaged but not cited — see Sources & references.

Mutation analysis of BRCA1 and BRCA2 from 793 Korean patients with sporadic breast cancer.

PMID 17100994 ↗ · Han SH et al. · 2006 Dec CLINVAR · case observation

Searched

c.1167G>ANP_000050.3:p.(P389=)P389P1395G>A

Found

The paper reports a BRCA2 exon 10 synonymous variant written as 1395G>A, p.P389P, corresponding to the queried synonymous amino-acid change notation, in 6 of 793 Korean patients with sporadic breast cancer and none of 167 normal controls; it was classified as a polymorphism and no variant-specific functional or segregation assay was reported.

Variant

✓ Names this variant — characterised directly

Applied to

→BS1 supporting

The reported control observation provides corroborative population-frequency context for benign evidence, but does not replace the governing ENIGMA gnomAD FAF rule.

10 1395G.Ac P389P P 6 3 None

Location Table 2, Sequence alterations detected in BRCA2, Polymorphisms · Context 793 Korean patients with sporadic breast cancer and 167 normal controls; BRCA1/BRCA2 coding exons and exon-intron boundaries were screened by DHPLC and sequencing. · full text

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

20104584 ↗ Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. CLINVAR

25741868 ↗ 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. CLINVAR

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

12692171 ↗ American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. CLINVAR

16949048 ↗ Identification of BRCA1 and BRCA2 mutations from Korean breast cancer patients using denaturing HPLC. CLINVAR

20301425 ↗ BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer. CLINVAR

21232165 ↗ The occurrence of germline BRCA1 and BRCA2 sequence alterations in Slovenian population. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

Check your email

Reset your password

Enter an access code

Your allowance