chr17-43063808-C-T

Variant names:

• chr17-43063808-C-T
• rs3092994
• NM_007294.4:c.5152+66G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007294.4(BRCA1):​c.5152+66G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,326,596 control chromosomes in the GnomAD database, including 76,364 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7707 hom., cov: 32)
  • Exomes 𝑓: 0.34 (68657 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:18 O:2
• Conservation: PhyloP100: -0.517
• Publications: 44 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, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P
• 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

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 17-43063808-C-T is Benign according to our data. Variant chr17-43063808-C-T is described in ClinVar as Benign. ClinVar VariationId is 55428.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

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.5152+66G>A		intron	N/A	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.5218+66G>A		intron	N/A	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.5218+66G>A		intron	N/A	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.5152+66G>A		intron	N/A	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.5215+66G>A		intron	N/A	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.5152+66G>A		intron	N/A	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47165 AN: 151838 Hom.: 7704 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.372

Gnomad SAS AF: 0.494

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.357

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.328

GnomAD4 exome AF: 0.336 AC: 394441 AN: 1174640 Hom.: 68657 AF XY: 0.342 AC XY: 204021 AN XY: 596304

African (AFR) AF: 0.229 AC: 6310 AN: 27540

American (AMR) AF: 0.221 AC: 9396 AN: 42454

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 8835 AN: 24166

East Asian (EAS) AF: 0.353 AC: 13419 AN: 38044

South Asian (SAS) AF: 0.499 AC: 39345 AN: 78906

European-Finnish (FIN) AF: 0.397 AC: 20876 AN: 52636

Middle Eastern (MID) AF: 0.373 AC: 1915 AN: 5138

European-Non Finnish (NFE) AF: 0.324 AC: 277326 AN: 855082

Other (OTH) AF: 0.336 AC: 17019 AN: 50674

GnomAD4 genome AF: 0.311 AC: 47186 AN: 151956 Hom.: 7707 Cov.: 32 AF XY: 0.316 AC XY: 23462 AN XY: 74230

African (AFR) AF: 0.232 AC: 9614 AN: 41432

American (AMR) AF: 0.272 AC: 4145 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1242 AN: 3468

East Asian (EAS) AF: 0.371 AC: 1919 AN: 5170

South Asian (SAS) AF: 0.493 AC: 2376 AN: 4820

European-Finnish (FIN) AF: 0.404 AC: 4258 AN: 10532

Middle Eastern (MID) AF: 0.356 AC: 104 AN: 292

European-Non Finnish (NFE) AF: 0.332 AC: 22568 AN: 67964

Other (OTH) AF: 0.332 AC: 700 AN: 2110

Alfa AF: 0.306 Hom.: 3176

Bravo AF: 0.292

Asia WGS AF: 0.414 AC: 1438 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	Breast-ovarian cancer, familial, susceptibility to, 1 (7)
-	-	4	not specified (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	2	Hereditary breast ovarian cancer syndrome (2)
-	-	-	Familial cancer of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.46
PhyloP100		-0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=62/38	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs3092994; hg19: chr17-41215825; COSMIC: COSV58793783; COSMIC: COSV58793783;