VP-R-2026-001

BRCA1 c.5056C>T

Hereditary breast and ovarian cancer

Needs reviewCritical

Your DNA didn’t change. Science did. AI assists. Clinicians decide.

Classification change

2023 · On file

Uncertain significance

Reported 14 Mar 2023

Science evolves

Today · ClinVar

Likely pathogenic

ClinVar last evaluated 18 Aug 2025 · Reviewed by expert panel

The DNA has not changed. Only the interpretation has.BRCA1 c.5056C>T (p.His1686Tyr) · identical in both

Classification drift

Variant

Gene: BRCA1
HGVS (coding): c.5056C>T
Protein: p.His1686Tyr
ClinVar: VCV000531444
dbSNP: rs1555579648
Panel: Hereditary cancer panel
Molecular consequence: missense variant

How the interpretation changed

BRCA1 c.5056C>T. The DNA is unchanged. The evidence around it is not.

2023Genetic test performedFirst record on file carrying BRCA1 c.5056C>T.
2023Reported as uncertain significanceMissense change in the BRCT domain. Public submissions were limited and in agreement on uncertain significance at the time of reporting.
2024Further literature published2 indexed publications appeared after the original report.
2025Submissions accumulated10 independent submissions now contribute to the classification.
2025Classification now likely pathogenicLast evaluated 18 Aug 2025 · Reviewed by expert panel.
TodayVariantPulse identified the affected records4 historical records carry this variant and were flagged for clinical review.

Evidence summary draft

AI draft · clinician must review

Evidence summary

Decision support

Since the 2023 report, the consensus for BRCA1 c.5056C>T has moved from uncertain significance to likely pathogenic. That reading rests on 10 submissions at strong review confidence, reviewed by expert panel. That crosses the clinically actionable boundary, so management guidance issued on the original interpretation may no longer be the right guidance. 4 records on file carry this variant and have not yet been reassessed.

Composed from the structured fields of the records cited on this page. Requires clinical verification before it informs any decision.

Patient impact

The changed variant and every historical record that carries it. Select a record to see its detail.

Synthetic demonstration data

Changed variant

BRCA1

c.5056C>T

VUSLikely pathogenic

VP-10247

Not reviewed

45-54 · Clinical Genetics

Synthetic ID: VP-10247
Test date: 14 Mar 2023
Original classification: Uncertain significancereported 14 Mar 2023
Current evidence: Likely pathogenicClinVar, evaluated 18 Aug 2025
Clinical owner: Dr. L. Haddad
Review status: Not reviewed

Open record

Evidence by source

Each source is shown as it reports itself. VariantPulse does not merge them into a single verdict.

Source	Classification	Review level	Last updated	Strength
ClinVar10 submissions on record.	Likely pathogenic	Reviewed by expert panel	18 Aug 2025	Strong3 of 4 review criteria met	VCV000531444
Population frequencyHighest reported allele frequency carried on the source record.	Not reported	No frequency data	18 Aug 2025	Reference observation
LiteraturePublications linked to this variant record.	8 indexed publications	PubMed index	Latest 2024	Supporting context
Regional Evidence IndexModelled regional aggregation maintained inside this workspace	Likely pathogenic	0 regional observations	18 Feb 2026	Cohort 3,042
This institutionThe interpretation issued to the patient at the time of testing.	Uncertain significance	Internal report	14 Mar 2023	On record

Cited publications

Evidence-based recommendations for gene-specific ACMG/AMP variant classification from the ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel. · Am J Hum Genet 2024 · PMID 39142283
Defining and Reducing Variant Classification Disparities. · medRxiv 2024 · PMID 38645101
ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG). · Genet Med 2022 · PMID 35802134
Closing the gap: Systematic integration of multiplexed functional data resolves variants of uncertain significance in BRCA1, TP53, and PTEN. · Am J Hum Genet 2021 · PMID 34793697
Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. · Ann Oncol 2021 · PMID 34242744
ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG). · Genet Med 2021 · PMID 34012068
Risk assessment and genetic counseling for hereditary breast and ovarian cancer syndromes-Practice resource of the National Society of Genetic Counselors. · J Genet Couns 2021 · PMID 33410258
Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA1/2-Related Cancer in Women: A Systematic Review for the U.S. Preventive Services Task Force · Agency for Healthcare Research and Quality (US) 2019 · PMID 31479213

Global and regional evidence

Sources agree

Global · ClinVar

Likely pathogenic

reviewed by expert panel · Last evaluated 18 Aug 2025

Regional · Regional Evidence Index

Likely pathogenic

0 observations in 3,042 · updated 18 Feb 2026

Sources consistent

Both lanes fall in the same clinical band.

Both sources place this variant in the same band.

Global

Likely pathogenic

Submissions: 10
Review status: Reviewed by expert panel
Last evaluated: 18 Aug 2025
Reference frequency: Not reported

Read from ClinVar, which aggregates submissions dominated by European-ancestry cohorts.

Regional

Likely pathogenic

Observations: 0
Cohort size: 3,042
Last updated: 18 Feb 2026
Regional frequency: 0.00e+0

Modelled regional aggregation maintained inside this workspace.

VariantPulse analysis

Both sources place this variant in the same band, so there is no divergence to resolve. Absent from gnomAD v4 entirely, including its ~3,000 Middle Eastern individuals. Regional data neither supports nor contradicts the expert-panel reclassification; the global reading stands.

Ancestry-informative markers and variants of uncertain significance on hereditary cancer panels. · Front Oncol 2026 · PMID 42137137
Middle Eastern Genetic Variation Improves Clinical Annotation of the Human Genome. · J Pers Med 2022 · PMID 35330423

How VariantPulse reached this resultEight steps, each one inspectable

1Historical record retrievedBRCA1 c.5056C>T reported as Uncertain significance on 2023-03-14.
2Variant normalisedResolved to ClinVar VCV000531444 (rs1555579648) and keyed as BRCA1:c.5056C>T.
3Current evidence retrievedRead live from ClinVar: Likely pathogenic, 10 submissions, reviewed by expert panel.
4Classification difference detectedRecorded interpretation normalised to Uncertain significance. Current interpretation normalised to Likely pathogenic. The interpretation crossed into the clinically actionable band, so records carrying it may need review.
5Regional sources comparedRegional index asserts Likely pathogenic, consistent with the global reading.
6Impacted records identified12,482 findings checked; 4 carry this variant.
7Evidence brief generatedComposed from the structured fields of the cited records above.
8Human review requestedVariantPulse does not change any record. A clinician decides what happens next.

Review priority

A triage signal for the queue. Not a clinical risk score, and not a statement about any individual.

+60Moved into the actionable bandUncertain significance to Likely pathogenic.
+204 records on fileHistorical results carrying this variant that a reviewer would reassess.
+10High review confidenceThe current classification carries expert-panel or guideline review.

Ordering score90

Case trail

Every review action on this case, with who took it and when.

No review actions on this case yet.

Recommendation

Reassess 4 records against the current interpretation and decide whether the reporting clinician should be notified. Final interpretation remains with the clinical team.

Review actions

Each action is recorded in the audit trail. None changes a classification or a diagnosis.

Assign reviewer

Clinician note

Decision

A decision needs a clinician note of at least 10 characters. It records the outcome of the review; it does not write to any patient record or issue a diagnosis.

Case detail

Case: VP-R-2026-001
Raised: 2m ago
Assigned: Unassigned
Evidence source: ClinVar · Evidence monitor live
Records impacted: 4

Decision support only. Final interpretation remains with the qualified clinical team.

Affected records in full

Synthetic demonstration data

Record	Age band	Test date	As reported	Current	Department	Clinical owner	Last contact	Review state
VP-10247	45-54	14 Mar 2023	VUS	Likely pathogenic	Clinical Genetics	Dr. L. Haddad	4y ago	Not reviewed
VP-10284	35-44	9 May 2023	VUS	Likely pathogenic	Breast Surgery	Dr. N. Farouk	3y ago	Not reviewed
VP-10321	55-64	21 Aug 2023	VUS	Likely pathogenic	Oncology	Dr. R. Okonjo	3y ago	Not reviewed
VP-10358	25-34	2 Nov 2023	VUS	Likely pathogenic	Clinical Genetics	Dr. L. Haddad	3y ago	Not reviewed

Source

Classification

Review level

Last updated

Strength

ClinVar10 submissions on record.

Likely pathogenic

Reviewed by expert panel

18 Aug 2025

Strong

VCV000531444

Population frequencyHighest reported allele frequency carried on the source record.

Not reported

No frequency data

18 Aug 2025

Reference observation

LiteraturePublications linked to this variant record.

8 indexed publications

PubMed index

Latest 2024

Supporting context

Regional Evidence IndexModelled regional aggregation maintained inside this workspace

Likely pathogenic

0 regional observations

18 Feb 2026

Cohort 3,042

This institutionThe interpretation issued to the patient at the time of testing.

Uncertain significance

Internal report

14 Mar 2023

On record

Record

Age band

Test date

As reported

Current

Department

Clinical owner

Last contact

Review state

VP-10247

45-54

14 Mar 2023

VUS

Likely pathogenic

Clinical Genetics

Dr. L. Haddad

4y ago

Not reviewed

VP-10284

35-44

9 May 2023

VUS

Likely pathogenic

Breast Surgery

Dr. N. Farouk

3y ago

Not reviewed

VP-10321

55-64

21 Aug 2023

VUS

Likely pathogenic

Oncology

Dr. R. Okonjo

3y ago

Not reviewed

VP-10358

25-34

2 Nov 2023

VUS

Likely pathogenic

Clinical Genetics

Dr. L. Haddad

3y ago

Not reviewed