chr17-43125988-G-GTGT

Variant names:

• chr17-43125988-G-GTGT
• rs8176071
• ENST00000356906.8:n.351+218_351+219insTGT

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001408458.1(BRCA1):​c.-61-10212_-61-10210dupACA variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene BRCA1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.32 (7886 hom., cov: 0)
• Consequence: BRCA1 NM_001408458.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.457
• Publications: 9 publications found

Genes affected

NBR2 (HGNC:20691): (neighbor of BRCA1 lncRNA 2) This gene was identified by its close proximity on chromosome 17 to tumor suppressor gene BRCA1. Experimental evidence indicates that the two genes share a bi-directional promoter. Transcription for either gene is controlled individually by distinct transcriptional repressor factors. A short (112 amino acid) open reading frame is observed which includes a region derived from a LINE1 element. A strong Kozak signal is not observed for the putative ORF and the stop codon is more than 55 nucleotides upstream of the last splice site for the transcript, suggesting that the transcript is subject to nonsense-mediated decay. Therefore, this gene does not appear to encode a protein. Glucose starvation induces the expression of this gene and the long non-coding RNA transcribed by it functions with AMP-activated protein kinase in mediating the energy stress response. [provided by RefSeq, Aug 2016]

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: Benign. The variant received -8 ACMG points.

• 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_001408458.1. 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_001408458.1		c.-61-10212_-61-10210dupACA		intron	N/A	NP_001395387.1	B4DES0
	NBR2	NR_003108.2		n.214+220_214+222dupGTT		intron	N/A
	NBR2	NR_138145.1		n.214+220_214+222dupGTT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBR2	ENST00000356906.8	TSL:1	n.351+218_351+219insTGT		intron	N/A
	BRCA1	ENST00000634433.2	TSL:5	c.-19-1874_-19-1873insACA		intron	N/A	ENSP00000489431.2	A0A0U1RRA9
	NBR2	ENST00000460115.5	TSL:2	n.161+218_161+219insTGT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.316 AC: 47977 AN: 151752 Hom.: 7880 Cov.: 0

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.367

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.350

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.333

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.316 AC: 48011 AN: 151870 Hom.: 7886 Cov.: 0 AF XY: 0.322 AC XY: 23925 AN XY: 74200

African (AFR) AF: 0.233 AC: 9636 AN: 41434

American (AMR) AF: 0.331 AC: 5050 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1245 AN: 3472

East Asian (EAS) AF: 0.367 AC: 1891 AN: 5154

South Asian (SAS) AF: 0.492 AC: 2371 AN: 4816

European-Finnish (FIN) AF: 0.402 AC: 4238 AN: 10536

Middle Eastern (MID) AF: 0.349 AC: 102 AN: 292

European-Non Finnish (NFE) AF: 0.332 AC: 22507 AN: 67874

Other (OTH) AF: 0.337 AC: 711 AN: 2108

Alfa AF: 0.314 Hom.: 803

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.46

Splicing

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

Other links and lift over

dbSNP: rs8176071; hg19: chr17-41278005; COSMIC: COSV58789345;