NM_007294.4:c.548-58delT

Variant names:

• chr17-43097346-TA-T
• rs8176144
• NM_007294.4:c.548-58delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_007294.4(BRCA1):​c.548-58delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.328 in 1,330,490 control chromosomes in the GnomAD database, including 75,741 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7389 hom., cov: 0)
  • Exomes 𝑓: 0.33 (68352 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel U:2 B:9
• Conservation: PhyloP100: 0.898
• Publications: 22 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

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 17-43097346-TA-T is Benign according to our data. Variant chr17-43097346-TA-T is described in ClinVar as Benign. ClinVar VariationId is 125889.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.475 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.548-58delT		intron	N/A	NP_009225.1	P38398-1
	BRCA1	NM_001407581.1		c.548-58delT		intron	N/A	NP_001394510.1	A0A2R8Y7V5
	BRCA1	NM_001407582.1		c.548-58delT		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.548-58delT		intron	N/A	ENSP00000350283.3	P38398-1
	BRCA1	ENST00000471181.7	TSL:1	c.548-58delT		intron	N/A	ENSP00000418960.2	P38398-7
	BRCA1	ENST00000470026.6	TSL:1	c.548-58delT		intron	N/A	ENSP00000419274.2	P38398-1

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45538 AN: 151888 Hom.: 7387 Cov.: 0

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.321

GnomAD4 exome AF: 0.332 AC: 390779 AN: 1178484 Hom.: 68352 AF XY: 0.338 AC XY: 202633 AN XY: 599366

African (AFR) AF: 0.172 AC: 4757 AN: 27720

American (AMR) AF: 0.314 AC: 13622 AN: 43348

Ashkenazi Jewish (ASJ) AF: 0.356 AC: 8638 AN: 24236

East Asian (EAS) AF: 0.351 AC: 13460 AN: 38350

South Asian (SAS) AF: 0.497 AC: 39488 AN: 79492

European-Finnish (FIN) AF: 0.396 AC: 21006 AN: 53046

Middle Eastern (MID) AF: 0.362 AC: 1822 AN: 5028

European-Non Finnish (NFE) AF: 0.317 AC: 271278 AN: 856430

Other (OTH) AF: 0.329 AC: 16708 AN: 50834

GnomAD4 genome AF: 0.300 AC: 45545 AN: 152006 Hom.: 7389 Cov.: 0 AF XY: 0.307 AC XY: 22773 AN XY: 74280

African (AFR) AF: 0.180 AC: 7462 AN: 41460

American (AMR) AF: 0.319 AC: 4874 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 1213 AN: 3472

East Asian (EAS) AF: 0.369 AC: 1907 AN: 5174

South Asian (SAS) AF: 0.492 AC: 2372 AN: 4824

European-Finnish (FIN) AF: 0.405 AC: 4266 AN: 10546

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.330 AC: 22405 AN: 67952

Other (OTH) AF: 0.325 AC: 687 AN: 2114

Alfa AF: 0.306 Hom.: 900

Bravo AF: 0.282

Asia WGS AF: 0.406 AC: 1410 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.90
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs8176144; hg19: chr17-41249363; COSMIC: COSV58788493; COSMIC: COSV58788493;