17-43063930-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 PM1 PM5 PP3_Moderate PP5_Very_Strong

The NM_007294.4(BRCA1):​c.5096G>A​(p.Arg1699Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1699G) has been classified as Uncertain significance. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• 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:50 U:2 O:1
• Conservation: PhyloP100: 4.86
• Publications: 155 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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

ACMG classification

Specifications for BRCA1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: 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: In a hotspot region, there are 30 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 68 uncertain in NM_007294.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43063931-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 55396.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.841
• PP5: Variant 17-43063930-C-T is Pathogenic according to our data. Variant chr17-43063930-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 37636.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG 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	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

Sel.	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: 2 AN: 152020 Hom.: 0 Cov.: 32

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: 6 AN: 251262 AF XY: 0.0000221

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: 28 AN: 1461796 Hom.: 0 Cov.: 31 AF XY: 0.0000165 AC XY: 12 AN XY: 727212

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39678

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000207 AC: 23 AN: 1111956

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152020 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74246

African (AFR) AF: 0.00 AC: 0 AN: 41374

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
15	-	-	not provided (15)
13	1	-	Breast-ovarian cancer, familial, susceptibility to, 1 (14)
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

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
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
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		4.9
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.058	T
Polyphen		0.99	D
Vest4		0.96
MVP		0.97
MPC		0.39
ClinPred		0.95	D
GERP RS		5.8
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)

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

Other links and lift over

dbSNP: rs41293459; hg19: chr17-41215947; COSMIC: COSV58797961; COSMIC: COSV58797961;