chr17-43106527-GCA-ACT

Variant names:

• chr17-43106527-GCA-ACT
• NM_007294.4:c.139_141delTGCinsAGT
• BRCA1 p.Cys47Ser

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+5 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 5 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO5_ModerateO7_Supporting

The NM_007294.4(BRCA1):c.139_141delTGCinsAGT (p.Cys47Ser) variant causes a missense change. The gene BRCA1 is a tumor suppressor gene (CancerMine: 412 TSG, 22 oncogene, 49 driver citations). The gene BRCA1 is a cancer driver gene (CancerMine: 412 TSG, 22 oncogene, 49 driver citations). Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.C47G: Likely_pathogenic (ClinVar VariationId 54242, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.C47= (synonymous): Likely_benign (ClinVar VariationId 427311, 3 stars); p.C47S: unknown significance (ClinVar VariationId 868217); p.C47W: unknown significance (ClinVar VariationId 865192)

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.84
• Publications: 0 publications found

Genes affected

BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]

BRCA1 Gene-Disease associations (from GenCC):

• BRCA1-related cancer predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), ClinGen
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2])
	O5Same location/impact as known oncogenic		Same AA change as established oncogenic variant (or germline P/LP in TSG) — Moderate (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: true | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 22 pathogenic, 16 benign (OR vs. background: 6.8); Variant does not impact splicing — splice-hotspot path not applicable

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRCA1 NM_007294.4	MANE Select	c.139_141delTGCinsAGT p.Cys47Ser	missense	N/A	Prot: NP_009225.1 UniProt:
	BRCA1 NM_001407581.1		c.139_141delTGCinsAGT p.Cys47Ser	missense	N/A	Prot: NP_001394510.1 UniProt:
	BRCA1 NM_001407582.1		c.139_141delTGCinsAGT p.Cys47Ser	missense	N/A	Prot: NP_001394511.1 UniProt:

BRCA1 NM_007294.4

MANE Select

HGVSc / HGVSpc.139_141delTGCinsAGTp.Cys47Ser

Exon rankN/A

missense

Prot: NP_009225.1UniProt: P38398-1

BRCA1 NM_001407581.1

HGVSc / HGVSpc.139_141delTGCinsAGTp.Cys47Ser

Exon rankN/A

missense

Prot: NP_001394510.1UniProt: A0A2R8Y7V5

BRCA1 NM_001407582.1

HGVSc / HGVSpc.139_141delTGCinsAGTp.Cys47Ser

Exon rankN/A

missense

Prot: NP_001394511.1UniProt: A0A2R8Y7V5

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	BRCA1 ENST00000357654.9	TSL:1MANE Select	c.139_141delTGCinsAGT p.Cys47Ser	missense	N/A	Prot: ENSP00000350283.3 UniProt:
	BRCA1 ENST00000471181.7	TSL:1	c.139_141delTGCinsAGT p.Cys47Ser	missense	N/A	Prot: ENSP00000418960.2 UniProt:
	BRCA1 ENST00000470026.6	TSL:1	c.139_141delTGCinsAGT p.Cys47Ser	missense	N/A	Prot: ENSP00000419274.2 UniProt:

BRCA1 ENST00000357654.9

TSL:1MANE Select

HGVSc / HGVSpc.139_141delTGCinsAGTp.Cys47Ser

Exon rankN/A

missense

Prot: ENSP00000350283.3UniProt: P38398-1

BRCA1 ENST00000471181.7

TSL:1

HGVSc / HGVSpc.139_141delTGCinsAGTp.Cys47Ser

Exon rankN/A

missense

Prot: ENSP00000418960.2UniProt: P38398-7

BRCA1 ENST00000470026.6

TSL:1

HGVSc / HGVSpc.139_141delTGCinsAGTp.Cys47Ser

Exon rankN/A

missense

Prot: ENSP00000419274.2UniProt: P38398-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Uncertain	4.8

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

2 abnormal

5 no calibration

7 assays found for this variant.

Clinical calibration: 2 functionally abnormal (PS3), 0 functionally normal (BS3).

No calibration: 5 assays (score only).

Nucleotide level

BRCA1 SGE Normalized Scores

Meta-analysis of urn:mavedb:00000097-a-1, urn:mavedb:00000097-b-1, urn:mavedb:00000097-c-1, urn:mavedb:00000097-d-1, urn:mavedb:00000097-e-1 and 21 others

• Gene: BRCA1
• Assay type: Cell fitness
• Mechanism: Molecular function
• Model system: Immortalized human cells (Homo sapiens)
• Score: -1.93

Classified as

PS3 strongFunctionally abnormalFayer calibration: Non-functional

+4 more calibrations

PS3 strongFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: Non-functional

PS3 strongFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: Non-functional

PS3 strongFunctionally abnormalRUO ExCALIBR calibration: PS3 Strong (7)

PS3 strongFunctionally abnormalRUO ExCALIBR calibration (ClinVar 2018): PS3 Strong (5)

Nucleotide level

BRCA1 SGE Normalized Scores

Meta-analysis of urn:mavedb:00000097-a-1, urn:mavedb:00000097-b-1, urn:mavedb:00000097-c-1, urn:mavedb:00000097-d-1, urn:mavedb:00000097-e-1 and 21 others

• Gene: BRCA1
• Assay type: Cell fitness
• Mechanism: Molecular function
• Model system: Immortalized human cells (Homo sapiens)
• Score: -0.900

Classified as

PS3 Functionally abnormalFayer calibration: Intermediate

+2 more calibrations

PS3 Functionally abnormalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: Intermediate

PS3 Functionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: Intermediate

Nucleotide level

Enrich2 nucleotide variant scores for BRCA1 Y2H

BRCA1 Y2H

• Gene: BRCA1
• Score: -2.63 · p.Cys46Ser (assay numbering)

No calibration data

This score is at or below the 1st percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Protein level

Enrich2 amino acid variant scores for BRCA1 Y2H

BRCA1 Y2H

• Gene: BRCA1
• Score: -1.58 · p.Cys46Ser (assay numbering)

No calibration data

This score is at approximately the 10th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Nucleotide level

Enrich2 nucleotide variant scores for BRCA1 E3

BRCA1 E3

• Gene: BRCA1
• Score: · p.Cys46Ser (assay numbering)

No calibration data

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Protein level

Enrich2 amino acid variant scores for BRCA1 E3

BRCA1 E3

• Gene: BRCA1
• Score: -3.23 · p.Cys46Ser (assay numbering)

No calibration data

This score is at approximately the 3th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Protein level

BRCA1 RING and BRCT domains mean HDR fluorescence score

BRCA1 RING and BRCT domains in homology-directed DNA repair

• Gene: BRCA1
• Score: -0.781 · p.Cys47Ser (assay numbering)

No calibration data

This score is at approximately the 12th percentile of all variants tested in this assay.

This score has not been calibrated against ACMG evidence — shown for context only, not as clinical evidence.

Other links and lift over

hg19: chr17-41258544;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar