Genetic Variant BRCA1:p.Arg1699Gln (chr17-43063930-C-T) – ACMG Classification: Pathogenic (19 pts)

Variant summary

Our verdict is 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 0.0000153. 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

Scores

Clinical Significance

Pathogenic reviewed by expert panel P:55U:2O:1

Conservation

PhyloP100: 4.86

Publications

155 publications found

Variant links:

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

BRCA1 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_007294.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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.

PS3

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).

PM1

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).

PM2

Rare in gnomAD for AD/XL gene (popmax AF below threshold) — PM2 Supporting; GnomAD popmax AF = 0.0000153 — borderline rare for AD+AR gene (base 0.0001, raised to 0.000118 by highest known P/LP ClinVar AF 0.000118) — PM2 supporting.

PM5

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)

PP3

Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).

PP5

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

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	NP_009225.1	P38398-1
BRCA1	NM_001407581.1		c.5162G>A	p.Arg1721Gln	missense	Exon 18 of 24	NP_001394510.1	A0A2R8Y7V5
BRCA1	NM_001407582.1		c.5162G>A	p.Arg1721Gln	missense	Exon 18 of 24	NP_001394511.1	A0A2R8Y7V5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.5096G>A	p.Arg1699Gln	missense	Exon 17 of 23	ENSP00000350283.3	P38398-1
BRCA1	ENST00000471181.7	TSL:1	c.5159G>A	p.Arg1720Gln	missense	Exon 18 of 24	ENSP00000418960.2	P38398-7
BRCA1	ENST00000470026.6	TSL:1	c.5096G>A	p.Arg1699Gln	missense	Exon 17 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000239

AC:

AN:

251262

AF XY:

0.0000221

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39678

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1111956

Other (OTH)

AF:

0.0000166

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152020

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41374

American (AMR)

AF:

0.00

AC:

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.000155

AC:

AN:

122562

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:reviewed by expert panel

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 1 (19)

not provided (15)

Hereditary breast ovarian cancer syndrome (10)

Hereditary cancer-predisposing syndrome (3)

Breast and/or ovarian cancer (2)

Familial cancer of breast (2)

BRCA1-related cancer predisposition (1)

BRCA1-related disorder (1)

Breast-ovarian cancer, familial, susceptibility to, 1;C2936783:Lynch syndrome 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)

Fanconi anemia, complementation group S (1)

Gastric cancer (1)

Ovarian neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.73

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.39

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.75

MetaRNN

Pathogenic

0.84

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.2

PhyloP100

4.9

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.1

REVEL

Pathogenic

0.79

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.058

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.88

Mutation Taster

=1/99

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

0.0

SpliceAI score (max)

0.15

Details are displayed if max score is > 0.2

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.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over