BRCA1 p.Arg1699Gln

Variant names:

• chr17-43063930-C-T
• rs41293459
• NM_007294.4:c.5096G>A
• BRCA1 p.Arg1699Gln

Your query was ambiguous. Multiple possible variants found:

• chr17-43063930-C-T
• chr17-43063929-CC-TT

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 9 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_StrongO3_SupportingO4_SupportingO5_SupportingO6_SupportingO7_Supporting

The NM_007294.4(BRCA1):c.5096G>A (p.Arg1699Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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). The variant allele was found at a cumulative frequency of 0.0000186 (AC=30) in the gnomAD database across 1,613,816 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.00002. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000839901: Several functional in vitro assays showed ambiguous results: the p.Arg1699Gln showed intermediate deleterious effects but not to the extend of a well -characterized pathogenic variant [PMID 22889855, 23867111, 21473589]." and additional evidence is available in 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) This exact variant is established as oncogenic in: CGI (Cancer Genome Interpreter). The variant has been observed in cBioPortal in 13 samples across 9 studies and 6 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.). 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: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:55 U:2 O:1
• Conservation: PhyloP100: 4.86
• Publications: 107 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: Likely_pathogenic. The variant received 9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		CGI exact DNA-change oncogenic — Strong (O1); TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (4.0 pts): CGI (Cancer Genome Interpreter), ClinVar germline P/LP in TSG (★★★)
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000020 — very rare (O3 supporting [+1])
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=13 | studies=9 | cancer types=6 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.
	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
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	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.5096G>A p.Arg1699Gln	missense	Exon 17 of 23	Prot: NP_009225.1 UniProt:
	BRCA1 NM_001407581.1		c.5162G>A p.Arg1721Gln	missense	Exon 18 of 24	Prot: NP_001394510.1 UniProt:
	BRCA1 NM_001407582.1		c.5162G>A p.Arg1721Gln	missense	Exon 18 of 24	Prot: NP_001394511.1 UniProt:

BRCA1 NM_007294.4

MANE Select

HGVSc / HGVSpc.5096G>Ap.Arg1699Gln

Exon rankExon 17 of 23

missense

Prot: NP_009225.1UniProt: P38398-1

BRCA1 NM_001407581.1

HGVSc / HGVSpc.5162G>Ap.Arg1721Gln

Exon rankExon 18 of 24

missense

Prot: NP_001394510.1UniProt: A0A2R8Y7V5

BRCA1 NM_001407582.1

HGVSc / HGVSpc.5162G>Ap.Arg1721Gln

Exon rankExon 18 of 24

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.5096G>A p.Arg1699Gln	missense	Exon 17 of 23	Prot: ENSP00000350283.3 UniProt:
	BRCA1 ENST00000471181.7	TSL:1	c.5159G>A p.Arg1720Gln	missense	Exon 18 of 24	Prot: ENSP00000418960.2 UniProt:
	BRCA1 ENST00000470026.6	TSL:1	c.5096G>A p.Arg1699Gln	missense	Exon 17 of 23	Prot: ENSP00000419274.2 UniProt:

BRCA1 ENST00000357654.9

TSL:1MANE Select

HGVSc / HGVSpc.5096G>Ap.Arg1699Gln

Exon rankExon 17 of 23

missense

Prot: ENSP00000350283.3UniProt: P38398-1

BRCA1 ENST00000471181.7

TSL:1

HGVSc / HGVSpc.5159G>Ap.Arg1720Gln

Exon rankExon 18 of 24

missense

Prot: ENSP00000418960.2UniProt: P38398-7

BRCA1 ENST00000470026.6

TSL:1

HGVSc / HGVSpc.5096G>Ap.Arg1699Gln

Exon rankExon 17 of 23

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000132	AC:2	Hom:0	AN:152020	Cov:32
GnomAD2 exomes	AF: 0.0000239	AC:6	Hom:	AN:251262	Cov:
GnomAD4 exome	AF: 0.0000192	AC:28	Hom:0	AN:1461796	Cov:31
GnomAD4 genome	AF: 0.0000132	AC:2	Hom:0	AN:152020	Cov:32
TOPMed (Bravo)	AF: 0.0000227	AC:6	Hom:0	AN:264690	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:137886	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ChinaMAP Phase 1	AF: 0.0000492	AC:	Hom:	AN:	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.000155	AC:19	Hom:0	AN:122562	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.000360 *	4	11112	0.000341 *	6	17618
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000693	2	28844
Epi25(Epilepsy)	0.0000238	1	41958	0.0000150	1	66888
SCHEMA(Schizophrenia)	0.0000530	6	113134	0.0000525	10	190576

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
18	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (19)
15	-	-	not provided (15)
9	-	-	Hereditary breast ovarian cancer syndrome (10)
3	-	-	Hereditary cancer-predisposing syndrome (3)
1	1	-	Breast and/or ovarian cancer (2)
2	-	-	Familial cancer of breast (2)
1	-	-	BRCA1-related cancer predisposition (1)
1	-	-	BRCA1-related disorder (1)
1	-	-	Breast-ovarian cancer, familial, susceptibility to, 1;C2936783:Lynch syndrome 1 (1)
1	-	-	Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S (1)
1	-	-	Fanconi anemia, complementation group S (1)
1	-	-	Gastric cancer (1)
1	-	-	Ovarian neoplasm (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	30
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.94	D
FuncVEP CTI	Pathogenic	0.99
GPN-Star LLR	N/A	-7.9
GPN-Star score	N/A	7.9
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	0.94	D
Mutation Taster	N/A	1/99	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.2	M
PhyloP100	Uncertain	4.9
popEVE	Benign	-4.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.1	D
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.058	T
Varity_R	N/A	0.97
VESM-3B	Benign	-11

Showing 30 of 30 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Uncertain	0.23
Pangolin loss	Uncertain	0.23	Position offset: 21
SpliceAI score (max)	Benign	0.15	Details are displayed if max score is > 0.2
Splicevardb	N/A	0.0

Showing 4 of 4 scores

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.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs41293459;

hg19: chr17-41215947;

COSMIC: COSV58797961;

COSMIC: COSV58797961;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar