chr17-43063930-C-T

Variant names:

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

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 19 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2_SupportingPM5PP3_ModeratePP5_Very_Strong

The NM_007294.4(BRCA1):c.5096G>A (p.Arg1699Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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). 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 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 19 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); 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].; SCV001156534: This variant has been shown to impact function (PMID:18036263, 23867111, 30257991, 30765603, 11157798).; SCV000693499: Experimental studies have shown that this missense change can disrupt several functional activities of the BRCA1 protein, including transactivation (PMID: 18036263, 17308087, 11157798), phosphopeptide binding (PMID: 21473589, 15133503, 15133502), and nuclear foci formation (PMID: 18036263).; SCV000887711: "In general, functional studies have shown that this variant causes a reduction in BRCA1 protein activity (PMIDs: 28781887 (2016), 23867111 (2013), 21946536 (2011), 20516115 (2010), 21473589 (2011), 17308087 (2007), 11157798 (2001))"; SCV001247343: PS3:Moderate; SCV004562806: Functional analyses of the variant protein show conflicting results, with significant reductions in transcriptional activation (Lovelock 2007) and protein interactions (Coquelle 2011), but retention of an intermediate level of homologous recombination activity (Bouwman 2013), altogether suggestive of a hypomorphic and damaging effect. PMID: 23867111 PMID: 21473589 PMID: 24504028; SCV000186568: "In one functional study, the p.R1699Q alteration was shown to destabilize the BRCT domain of the BRCA1 protein and demonstrated reduced, but not abolished, BRCA1 activity (Lovelock PK et al. Breast Cancer Res. 2007;9:R82)."; SCV000683252: Functional studies have reported that this variant impairs BRCA1 function in transcription activation, cisplatin and PARP inhibitor sensitivity, and homology-directed DNA repair assays (PMID: 11157798, 30458859, 30765603, 32546644).; SCV000076803: Experimental studies have shown that this missense change can disrupt several functional activities of the BRCA1 protein, including transactivation (PMID: 18036263, 17308087, 11157798), phosphopeptide binding (PMID: 21473589, 15133503, 15133502), and nuclear foci formation (PMID: 18036263).; SCV000605739: While some studies have demonstrated impaired in vitro protein activity, others report that the variant performed similar to wild-type (Williams 2003, Lovelock 2007, Chang 2011).; SCV000699200: Multiple independent functional studies reporting this variant have demonstrated: 1. proper or reduced BRCT domain folding, 2. loss of phosphopeptide binding, 3. decreased or intermediate transcriptional activity of the mutant BRCA1 constructs expressed in mammalian cell lines, and 4. defective homology-directed DNA repair (HDR) capacity and nuclear foci formation in mammalian cells, but preserved wild-type centrosome amplification function (Vallon-Christersson 2001, Williams 2003, Williams 2004, Carvalho 2007, Lovelock 2007, Rowling 2010, Lee 2010, Petitalot 2018, Langerud 2018).; SCV005045701: 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].; SCV005373753: Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:30257991, 32546644, 30765603) (PS3 met).; SCV004734896: Functional studies suggest that this variant may impair protein function (Lovelock et al. 2007. PubMed ID: 18036263; Lee et al. 2010. PubMed ID: 20516115; Bouwman et al. 2013. PubMed ID: 23867111).; SCV004817593: Functional studies have reported that this variant partially to fully impacts BRCA1 function in homology-directed repair and cisplatin sensitivity assays (PMID: 23867111, 28398198) and transcription activation and phosphopeptide binding assays (PMID: 11157798, 15133502, 15133503, 18036263, 20516115).
	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		Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.00002 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000118 by highest known P/LP ClinVar AF 0.000118) — PM2 supporting.
	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.R1699L: Likely_pathogenic (ClinVar VariationId 55398, 2 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)
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar ≥3 stars pathogenic — very strong (PP5); ClinVar submissions overwhelmingly pathogenic (≥10 total, ≥80% P/LP, <10% B/LB) — strong (PP5, count-based); ClinVar germline classification: Pathogenic/Likely Pathogenic, 3 star(s). ClinVar submissions strongly and reliably favor pathogenicity (53/55 total P/LP).

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

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