rs8176218

Variant names:

• chr17-43071521-G-GAATGTTCACTGTAACAATGCTTGT
• rs8176218
• NM_007294.4:c.4676-284_4676-283insACAAGCATTGTTACAGTGAACATT

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.4676-284_4676-283insACAAGCATTGTTACAGTGAACATT variant causes a intron change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.32 (7961 hom., cov: 0)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:2
• Conservation: PhyloP100: -0.489
• Publications: 6 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 17-43071521-G-GAATGTTCACTGTAACAATGCTTGT is Benign according to our data. Variant chr17-43071521-G-GAATGTTCACTGTAACAATGCTTGT is described in ClinVar as Benign. ClinVar VariationId is 264795.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.4676-284_4676-283insACAAGCATTGTTACAGTGAACATT		intron	N/A	NP_009225.1
	BRCA1	NM_001407581.1		c.4742-284_4742-283insACAAGCATTGTTACAGTGAACATT		intron	N/A	NP_001394510.1
	BRCA1	NM_001407582.1		c.4742-284_4742-283insACAAGCATTGTTACAGTGAACATT		intron	N/A	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.4676-284_4676-283insACAAGCATTGTTACAGTGAACATT		intron	N/A	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.4739-284_4739-283insACAAGCATTGTTACAGTGAACATT		intron	N/A	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.4676-284_4676-283insACAAGCATTGTTACAGTGAACATT		intron	N/A	ENSP00000419274.2

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48127 AN: 151834 Hom.: 7955 Cov.: 0

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.328

Gnomad ASJ AF: 0.358

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.354

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: 0.317 AC: 48161 AN: 151952 Hom.: 7961 Cov.: 0 AF XY: 0.323 AC XY: 24013 AN XY: 74272

African (AFR) AF: 0.235 AC: 9728 AN: 41412

American (AMR) AF: 0.329 AC: 5015 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.358 AC: 1243 AN: 3468

East Asian (EAS) AF: 0.370 AC: 1917 AN: 5180

South Asian (SAS) AF: 0.492 AC: 2366 AN: 4808

European-Finnish (FIN) AF: 0.404 AC: 4255 AN: 10542

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22562 AN: 67972

Other (OTH) AF: 0.337 AC: 712 AN: 2112

Alfa AF: 0.306 Hom.: 894

Asia WGS AF: 0.417 AC: 1447 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Sep 28, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.3598 (European), 0.2209 (African), 0.3746 (Admixed American/Latino), 0.372 (East Asian), 0.498 (South Asian), derived from 1000 genomes (2013-05-02).

not provided Benign:1

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs8176218; hg19: chr17-41223538;