rs5820483

Positions:

• chr17-43095105-A-ACCT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_007294.4(BRCA1):​c.671-246_671-245insAGG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.34 (8767 hom., cov: 0)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:3 O:1
• Conservation: PhyloP100: -0.607

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 17-43095105-A-ACCT is Benign according to our data. Variant chr17-43095105-A-ACCT is described in ClinVar as [Benign]. Clinvar id is 127125.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.671-246_671-245insAGG		intron_variant		ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.671-246_671-245insAGG		intron_variant		1	NM_007294.4	ENSP00000350283	P4

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51143 AN: 151596 Hom.: 8758 Cov.: 0

Gnomad AFR AF: 0.312

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.336

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.492

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.353

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

GnomAD4 genome AF: 0.337 AC: 51183 AN: 151716 Hom.: 8767 Cov.: 0 AF XY: 0.343 AC XY: 25395 AN XY: 74106

Gnomad4 AFR AF: 0.312

Gnomad4 AMR AF: 0.336

Gnomad4 ASJ AF: 0.347

Gnomad4 EAS AF: 0.368

Gnomad4 SAS AF: 0.491

Gnomad4 FIN AF: 0.401

Gnomad4 NFE AF: 0.330

Gnomad4 OTH AF: 0.356

Alfa AF: 0.330 Hom.: 882

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:2

Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jan 12, 2015	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.33 (Asian), 0.32 (African), 0.35 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Familial cancer of breast Other:1

not provided, no classification provided

literature only

Genomic Research Center, Shahid Beheshti University of Medical Sciences

-

- -

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: rs5820483; hg19: chr17-41247122;