17-43063929-CC-AA

Variant names:

• chr17-43063929-CC-AA
• NM_007294.4:c.5096_5097delGGinsTT
• BRCA1 p.Arg1699Leu

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 14 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2PM5

The NM_007294.4(BRCA1):c.5096_5097delGGinsTT (p.Arg1699Leu) variant causes a missense change. 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.R1699Q: Pathogenic (ClinVar VariationId 37636, 3 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) The same amino acid change has been reported as oncogenic or likely oncogenic in a clinical somatic variant database. This exact variant is curated in the UniProt human variants database as Uncertain Significance, associated with Breast-ovarian cancer, familial, susceptibility to, 1 (brovca1); it is also listed as a COSMIC curated somatic variant.

• 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 ACMG Germline Pathogenicity v2019

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: Pathogenic. The variant received 14 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 2 stars).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 32 pathogenic, 8 benign (OR vs. background: 19.1).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (base 0.0001, raised to 0.000118 by highest known P/LP ClinVar AF 0.000118) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.R1699Q: Pathogenic (ClinVar VariationId 37636, 3 stars); Other variants at the same amino acid residue (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)

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_5097delGGinsTT p.Arg1699Leu	missense	N/A	Prot: NP_009225.1 UniProt:
	BRCA1 NM_001407581.1		c.5162_5163delGGinsTT p.Arg1721Leu	missense	N/A	Prot: NP_001394510.1 UniProt:
	BRCA1 NM_001407582.1		c.5162_5163delGGinsTT p.Arg1721Leu	missense	N/A	Prot: NP_001394511.1 UniProt:

BRCA1 NM_007294.4

MANE Select

HGVSc / HGVSpc.5096_5097delGGinsTTp.Arg1699Leu

Exon rankN/A

missense

Prot: NP_009225.1UniProt: P38398-1

BRCA1 NM_001407581.1

HGVSc / HGVSpc.5162_5163delGGinsTTp.Arg1721Leu

Exon rankN/A

missense

Prot: NP_001394510.1UniProt: A0A2R8Y7V5

BRCA1 NM_001407582.1

HGVSc / HGVSpc.5162_5163delGGinsTTp.Arg1721Leu

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_5097delGGinsTT p.Arg1699Leu	missense	N/A	Prot: ENSP00000350283.3 UniProt:
	BRCA1 ENST00000471181.7	TSL:1	c.5159_5160delGGinsTT p.Arg1720Leu	missense	N/A	Prot: ENSP00000418960.2 UniProt:
	BRCA1 ENST00000470026.6	TSL:1	c.5096_5097delGGinsTT p.Arg1699Leu	missense	N/A	Prot: ENSP00000419274.2 UniProt:

BRCA1 ENST00000357654.9

TSL:1MANE Select

HGVSc / HGVSpc.5096_5097delGGinsTTp.Arg1699Leu

Exon rankN/A

missense

Prot: ENSP00000350283.3UniProt: P38398-1

BRCA1 ENST00000471181.7

TSL:1

HGVSc / HGVSpc.5159_5160delGGinsTTp.Arg1720Leu

Exon rankN/A

missense

Prot: ENSP00000418960.2UniProt: P38398-7

BRCA1 ENST00000470026.6

TSL:1

HGVSc / HGVSpc.5096_5097delGGinsTTp.Arg1699Leu

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: -1.56

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: -0.981 · p.Arg27Leu (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: -0.981 · p.Arg27Leu (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 moderateFunctionally abnormalRUO ExCALIBR calibration: PS3 Moderate (2)

PS3 moderateFunctionally abnormalRUO ExCALIBR calibration (ClinVar 2018): 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: -1.03 · p.Arg123Leu (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 (5)

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

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: -1.03 · p.Arg123Leu (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

Submit to ClinVar