rs572766355

chr17-43056992-G-GGGAGTGGAATAC

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_007294.4(BRCA1):c.5277+59_5277+60insGTATTCCACTCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,469,986 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (1 hom.)
• Consequence: BRCA1 NM_007294.4 intron
• Clinical Significance: Benign reviewed by expert panel B:9
• Conservation: PhyloP100: 0.590

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 -8 ACMG points.

• BP6: Variant 17-43056992-G-GGGAGTGGAATAC is Benign according to our data. Variant chr17-43056992-G-GGGAGTGGAATAC is described in ClinVar as [Benign]. Clinvar id is 433729.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5277+59_5277+60insGTATTCCACTCC		intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5277+59_5277+60insGTATTCCACTCC		intron_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152130 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00113

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00323

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00239 AC: 3150 AN: 1317738 Hom.: 1 AF XY: 0.00232 AC XY: 1542 AN XY: 663324

Gnomad4 AFR exome AF: 0.000492

Gnomad4 AMR exome AF: 0.000786

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000960

Gnomad4 FIN exome AF: 0.00150

Gnomad4 NFE exome AF: 0.00300

Gnomad4 OTH exome AF: 0.00130

GnomAD4 genome AF: 0.00177 AC: 269 AN: 152248 Hom.: 1 Cov.: 31 AF XY: 0.00155 AC XY: 115 AN XY: 74422

Gnomad4 AFR AF: 0.000578

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00113

Gnomad4 NFE AF: 0.00323

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00184 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

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

Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000012 -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2021	This variant is associated with the following publications: (PMID: 18424508, 22366370, 7606717, 18489799, 8531967) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	BRCA1: BS3:Supporting, BS1 -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 30, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 10, 2016	- -

Hereditary breast ovarian cancer syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Nov 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Sep 12, 2023	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

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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: rs572766355; hg19: chr17-41209009;