17-43134805-T-G

Variant names:

• chr17-43134805-T-G
• rs2175957
• ENST00000356906.8:n.414+3535T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001408458.1(BRCA1):​c.-61-19026A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.319 in 151,852 control chromosomes in the GnomAD database, including 8,032 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (8032 hom., cov: 31)
• Consequence: BRCA1 NM_001408458.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.40
• Publications: 16 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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.478 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.-61-19026A>C		intron	N/A	NP_001395387.1	B4DES0
	NBR2	NR_003108.2		n.277+3535T>G		intron	N/A
	NBR2	NR_138145.1		n.584+1668T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBR2	ENST00000356906.8	TSL:1	n.414+3535T>G		intron	N/A
	BRCA1	ENST00000634433.2	TSL:5	c.-19-10690A>C		intron	N/A	ENSP00000489431.2	A0A0U1RRA9
	NBR2	ENST00000460115.5	TSL:2	n.224+3535T>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.319 AC: 48336 AN: 151734 Hom.: 8026 Cov.: 31

Gnomad AFR AF: 0.236

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.360

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.336

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

GnomAD4 genome AF: 0.319 AC: 48375 AN: 151852 Hom.: 8032 Cov.: 31 AF XY: 0.325 AC XY: 24102 AN XY: 74202

African (AFR) AF: 0.236 AC: 9761 AN: 41410

American (AMR) AF: 0.334 AC: 5092 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1260 AN: 3470

East Asian (EAS) AF: 0.371 AC: 1913 AN: 5160

South Asian (SAS) AF: 0.495 AC: 2382 AN: 4814

European-Finnish (FIN) AF: 0.404 AC: 4253 AN: 10522

Middle Eastern (MID) AF: 0.360 AC: 105 AN: 292

European-Non Finnish (NFE) AF: 0.333 AC: 22633 AN: 67900

Other (OTH) AF: 0.340 AC: 716 AN: 2108

Alfa AF: 0.264 Hom.: 1381

Bravo AF: 0.304

Asia WGS AF: 0.421 AC: 1462 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.1
DANN	Benign	0.31
PhyloP100		-1.4

Splicing

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

Other links and lift over

dbSNP: rs2175957; hg19: chr17-41286822;