chr17-43063929-CC-TG

Variant names:

• chr17-43063929-CC-TG
• NM_007294.4:c.5096_5097delGGinsCA
• BRCA1 p.Arg1699Pro

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+4 Uncertain · Hot

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 4 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO5_SupportingO7_Supporting

The NM_007294.4(BRCA1):c.5096_5097delGGinsCA (p.Arg1699Pro) 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.R1699L: Likely_pathogenic (ClinVar VariationId 55398, 2 stars) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.R1699G: unknown significance (ClinVar VariationId 869021); p.R1699P: Uncertain_significance (ClinVar VariationId 55397, 3 stars); p.R1699= (synonymous): Likely_benign (ClinVar VariationId 1745302, 1 star); p.R1699= (synonymous): Likely_benign (ClinVar VariationId 873409, 2 stars); p.R1699= (synonymous): Likely_benign (ClinVar VariationId 55395, 3 stars)

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.86
• 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 4 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		Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (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: false | 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: 32 pathogenic, 8 benign (OR vs. background: 19.1); 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.5096_5097delGGinsCA p.Arg1699Pro	missense	N/A	Prot: NP_009225.1 UniProt:
	BRCA1 NM_001407581.1		c.5162_5163delGGinsCA p.Arg1721Pro	missense	N/A	Prot: NP_001394510.1 UniProt:
	BRCA1 NM_001407582.1		c.5162_5163delGGinsCA p.Arg1721Pro	missense	N/A	Prot: NP_001394511.1 UniProt:

BRCA1 NM_007294.4

MANE Select

HGVSc / HGVSpc.5096_5097delGGinsCAp.Arg1699Pro

Exon rankN/A

missense

Prot: NP_009225.1UniProt: P38398-1

BRCA1 NM_001407581.1

HGVSc / HGVSpc.5162_5163delGGinsCAp.Arg1721Pro

Exon rankN/A

missense

Prot: NP_001394510.1UniProt: A0A2R8Y7V5

BRCA1 NM_001407582.1

HGVSc / HGVSpc.5162_5163delGGinsCAp.Arg1721Pro

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.5096_5097delGGinsCA p.Arg1699Pro	missense	N/A	Prot: ENSP00000350283.3 UniProt:
	BRCA1 ENST00000471181.7	TSL:1	c.5159_5160delGGinsCA p.Arg1720Pro	missense	N/A	Prot: ENSP00000418960.2 UniProt:
	BRCA1 ENST00000470026.6	TSL:1	c.5096_5097delGGinsCA p.Arg1699Pro	missense	N/A	Prot: ENSP00000419274.2 UniProt:

BRCA1 ENST00000357654.9

TSL:1MANE Select

HGVSc / HGVSpc.5096_5097delGGinsCAp.Arg1699Pro

Exon rankN/A

missense

Prot: ENSP00000350283.3UniProt: P38398-1

BRCA1 ENST00000471181.7

TSL:1

HGVSc / HGVSpc.5159_5160delGGinsCAp.Arg1720Pro

Exon rankN/A

missense

Prot: ENSP00000418960.2UniProt: P38398-7

BRCA1 ENST00000470026.6

TSL:1

HGVSc / HGVSpc.5096_5097delGGinsCAp.Arg1699Pro

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	4.9

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.

5 abnormal

5 assays found for this variant.

Clinical calibration: 5 functionally abnormal (PS3), 0 functionally normal (BS3).

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: -1.55

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)

Protein level

Scores from growth assay of BRCA1 variants

Growth assay of BRCA1 variants

• Gene: BRCA1
• Assay type: Cell fitness
• Mechanism: Cellular response to cisplatin, DNA repair and Double-strand break repair via homologous recombination
• Model system: Immortalized human cells (Homo sapiens)
• Score: -1.07 · p.Arg27Pro (assay numbering)

Classified as

PS3 moderateFunctionally abnormalInvestigator-provided functional classes: LOF

+2 more calibrations

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: LOF

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: LOF

Protein level

Scores from growth assay of BRCA1 variants

Growth assay of BRCA1 variants

• Gene: BRCA1
• Assay type: Cell fitness
• Mechanism: Cellular response to cisplatin, DNA repair and Double-strand break repair via homologous recombination
• Model system: Immortalized human cells (Homo sapiens)
• Score: -1.07 · p.Arg27Pro (assay numbering)

Classified as

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: LOF

+4 more calibrations

PS3 moderateFunctionally abnormalInvestigator-provided functional classes: LOF

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: Missense Variants Only: LOF

PS3 moderate plusFunctionally abnormalRUO ExCALIBR calibration (ClinVar 2018): PS3 Moderate+ (3)

PS3 moderateFunctionally abnormalRUO ExCALIBR calibration: PS3 Moderate (2)

Protein level

Scores from multiplexed functional assay of BRCA1 variants

Multiplexed functional assay of BRCA1 variants

• Gene: BRCA1
• Assay type: Reporter
• Mechanism: DNA repair and Double-strand break repair via homologous recombination
• Model system: Immortalized human cells (Homo sapiens)
• Score: -0.985 · p.Arg123Pro (assay numbering)

Classified as

PS3 moderateFunctionally abnormalIGVF Coding Variant Focus Group -- Controls: All Variants: LOF

+4 more calibrations

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

PS3 moderateFunctionally abnormalInvestigator-provided functional classes: LOF

PS3 strongFunctionally abnormalRUO ExCALIBR calibration: PS3 Strong (4)

PS3 strongFunctionally abnormalRUO ExCALIBR calibration (ClinVar 2018): PS3 Strong (4)

Protein level

Scores from multiplexed functional assay of BRCA1 variants

Multiplexed functional assay of BRCA1 variants

• Gene: BRCA1
• Assay type: Reporter
• Mechanism: DNA repair and Double-strand break repair via homologous recombination
• Model system: Immortalized human cells (Homo sapiens)
• Score: -0.985 · p.Arg123Pro (assay numbering)

Classified as

PS3 moderateFunctionally abnormalInvestigator-provided functional classes: LOF

+2 more calibrations

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

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

Other links and lift over

hg19: chr17-41215946;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

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