rs8176218

chr17-43071521-G-GAATGTTCACTGTAACAATGCTTGT

Variant summary

Our verdict is Benign. Variant got -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. The variant allele was found at a frequency of 0.317 in 151,952 control chromosomes in the GnomAD database, including 7,961 homozygotes. 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.4676-284_4676-283insACAAGCATTGTTACAGTGAACATT		intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4676-284_4676-283insACAAGCATTGTTACAGTGAACATT		intron_variant		1	NM_007294.4	P4

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

Gnomad4 AFR AF: 0.235

Gnomad4 AMR AF: 0.329

Gnomad4 ASJ AF: 0.358

Gnomad4 EAS AF: 0.370

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.332

Gnomad4 OTH AF: 0.337

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

Benign, reviewed by expert panel

curation

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

Sep 28, 2016

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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs8176218; hg19: chr17-41223538;