Genetic Variant BRCA1:p.Arg1699Leu (chr17-43063930-C-A) – ACMG Classification: Pathogenic (16 pts)

Variant summary

Our verdict is The variant received 16 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP3_ModeratePP5_Strong

The NM_007294.4(BRCA1):c.5096G>T (p.Arg1699Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. 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: "SCV004018696: Functional studies indicate this variant impacts protein function [PMID:30209399, 35196514]." 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.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) 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: not found (cov: 32)

Consequence

BRCA1
NM_007294.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2U: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:

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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 16 points.

PS3

Well-established functional study supports damaging effect (PS3); SCV004018696: Functional studies indicate this variant impacts protein function [PMID: 30209399, 35196514].; SCV001496381: Experimental studies have shown that this missense change affects BRCA1 function (PMID: 20516115, 25748678).

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

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.

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.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)

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 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

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>T	p.Arg1699Leu	missense	Exon 17 of 23	NP_009225.1	P38398-1
BRCA1	NM_001407581.1		c.5162G>T	p.Arg1721Leu	missense	Exon 18 of 24	NP_001394510.1	A0A2R8Y7V5
BRCA1	NM_001407582.1		c.5162G>T	p.Arg1721Leu	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>T	p.Arg1699Leu	missense	Exon 17 of 23	ENSP00000350283.3	P38398-1
BRCA1	ENST00000471181.7	TSL:1	c.5159G>T	p.Arg1720Leu	missense	Exon 18 of 24	ENSP00000418960.2	P38398-7
BRCA1	ENST00000470026.6	TSL:1	c.5096G>T	p.Arg1699Leu	missense	Exon 17 of 23	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000148

Hom.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Breast-ovarian cancer, familial, susceptibility to, 1 (2)

Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.46

BayesDel_noAF

Pathogenic

0.42

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Uncertain

0.95

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.87

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.2

PhyloP100

4.9

PrimateAI

Uncertain

0.73

PROVEAN

Pathogenic

-5.3

REVEL

Pathogenic

0.84

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.93

Mutation Taster

=0/100

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

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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BRCA1 p.Arg1699Leu

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over