ENST00000618469.2:c.-33_-29delAAAAA

Variant names:

• chr17-43124745-GTTTTT-G
• rs770929332
• ENST00000618469.2:c.-33_-29delAAAAA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The ENST00000618469.2(BRCA1):​c.-33_-29delAAAAA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00251 in 202,482 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (2 hom.)
• Consequence: BRCA1 ENST00000618469.2 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.182
• Publications: 1 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):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 17-43124745-GTTTTT-G is Benign according to our data. Variant chr17-43124745-GTTTTT-G is described in ClinVar as Likely_benign. ClinVar VariationId is 254638.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000618469.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.-20+521_-20+525delAAAAA		intron	N/A	NP_009225.1
	BRCA1	NM_001407583.1		c.-33_-29delAAAAA		5_prime_UTR	Exon 1 of 24	NP_001394512.1
	BRCA1	NM_001407591.1		c.-33_-29delAAAAA		5_prime_UTR	Exon 1 of 24	NP_001394520.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000618469.2	TSL:1	c.-33_-29delAAAAA		5_prime_UTR	Exon 1 of 23	ENSP00000478114.2
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.-20+521_-20+525delAAAAA		intron	N/A	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.-20+521_-20+525delAAAAA		intron	N/A	ENSP00000418960.2

Frequencies

GnomAD3 genomes AF: 0.00250 AC: 380 AN: 151902 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000653

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.000525

Gnomad ASJ AF: 0.00116

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000849

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00465

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.00254 AC: 128 AN: 50462 Hom.: 2 AF XY: 0.00245 AC XY: 68 AN XY: 27808

African (AFR) AF: 0.00107 AC: 1 AN: 936

American (AMR) AF: 0.000341 AC: 1 AN: 2930

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 4 AN: 924

East Asian (EAS) AF: 0.00 AC: 0 AN: 1770

South Asian (SAS) AF: 0.000107 AC: 1 AN: 9360

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 154

European-Non Finnish (NFE) AF: 0.00391 AC: 117 AN: 29948

Other (OTH) AF: 0.00157 AC: 4 AN: 2544

GnomAD4 genome AF: 0.00250 AC: 380 AN: 152020 Hom.: 0 Cov.: 31 AF XY: 0.00227 AC XY: 169 AN XY: 74322

African (AFR) AF: 0.000651 AC: 27 AN: 41452

American (AMR) AF: 0.000525 AC: 8 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00116 AC: 4 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.000849 AC: 9 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00465 AC: 316 AN: 67976

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.00270 Hom.: 0

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:1

May 01, 2016

Department of Medical Genetics, University Hospital of North Norway

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.18

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs770929332; hg19: chr17-41276762;