chr17-43049113-A-G

Position:

• chr17-43049113-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_007294.4(BRCA1):​c.5406+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000855 in 1,613,446 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (10 hom., cov: 31)
  • Exomes 𝑓: 0.00046 (7 hom.)
• Consequence: BRCA1 NM_007294.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001104
• Clinical Significance: Benign reviewed by expert panel B:30 O:1
• Conservation: PhyloP100: 0.825

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-43049113-A-G is Benign according to our data. Variant chr17-43049113-A-G is described in ClinVar as [Benign]. Clinvar id is 125843.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43049113-A-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00468 (713/152260) while in subpopulation AFR AF= 0.0159 (660/41562). AF 95% confidence interval is 0.0149. There are 10 homozygotes in gnomad4. There are 334 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.5406+8T>C		splice_region_variant, intron_variant		ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.5406+8T>C		splice_region_variant, intron_variant		1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.00458 AC: 697 AN: 152142 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0155

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00116 AC: 292 AN: 251356 Hom.: 4 AF XY: 0.000847 AC XY: 115 AN XY: 135850

Gnomad AFR exome AF: 0.0148

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000456 AC: 667 AN: 1461186 Hom.: 7 Cov.: 31 AF XY: 0.000442 AC XY: 321 AN XY: 726938

Gnomad4 AFR exome AF: 0.0148

Gnomad4 AMR exome AF: 0.00125

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00468 AC: 713 AN: 152260 Hom.: 10 Cov.: 31 AF XY: 0.00449 AC XY: 334 AN XY: 74442

Gnomad4 AFR AF: 0.0159

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00235 Hom.: 3

Bravo AF: 0.00522

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:30 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:8 Other:1

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 0.02033 (African), derived from 1000 genomes (2012-04-30). -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jul 19, 2006	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jul 23, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	literature only	Counsyl	Apr 28, 2014	- -
not provided, no classification provided	in vitro	Brotman Baty Institute, University of Washington	-	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 07, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	May 31, 2017	- -

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Oct 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 02, 2014	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 09, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Feb 04, 2016	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 21, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Dec 08, 2017	- -

Hereditary breast ovarian cancer syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 14, 2014	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 30209399) -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 17, 2017

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA1 c.5406+8T>C variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was also identified in dbSBP (ID: rs55946644) as other, ClinVar (8x benign: ENIGMA, Invitae, Vantari Genetics, LabCorp, Baylor Miraca Genetics, Counsyl, Emory Genetics, BIC; 2x likely benign: Illumina, CHEO), Genesight-COGR (classified as benign by a clinical laboratory), LOVD 3.0 (7 entries, 2x predicted neutral, 1x no splicing defect), BIC Database (16x not pathogenic/low clinical significance, MAF>0.01) databases. The variant was not identified in the COSMIC, MutDB, UMD-LSDB, ARUP Laboratories, or Zhejiang University databases. The variant was also identified by our laboratory in 2 individuals with breast cancer. The variant was identified in control databases in 400 of 277096 chromosomes at a frequency of 0.001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 351 of 24014 chromosomes (freq: 0.015). Functional studies using splicing reporter minigene assays and patient RNA analysis indicate no effect on splicing (Steffensen 2014, Bonnet 2008, Thery 2011, Houdayer 2012). The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	3.6
DANN	Benign	0.62

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.032
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs55946644; hg19: chr17-41201130; COSMIC: COSV104621550;