17-43093220-A-G

Position:

• chr17-43093220-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_007294.4(BRCA1):​c.2311T>C​(p.Leu771Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,613,608 control chromosomes in the GnomAD database, including 91,981 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.30 (7355 hom., cov: 32)
  • Exomes 𝑓: 0.34 (84626 hom.)
• Consequence: BRCA1 NM_007294.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:30 O:2
• Conservation: PhyloP100: -0.442

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-43093220-A-G is Benign according to our data. Variant chr17-43093220-A-G is described in ClinVar as [Benign]. Clinvar id is 125554.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093220-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.442 with no splicing effect.
• 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	Protein	UniProt
BRCA1	NM_007294.4	c.2311T>C	p.Leu771Leu	synonymous_variant	10/23	ENST00000357654.9	NP_009225.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA1	ENST00000357654.9	c.2311T>C	p.Leu771Leu	synonymous_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45482 AN: 151856 Hom.: 7352 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.319

Gnomad ASJ AF: 0.349

Gnomad EAS AF: 0.369

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.403

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.330

Gnomad OTH AF: 0.319

GnomAD3 exomes AF: 0.347 AC: 87177 AN: 250946 Hom.: 16057 AF XY: 0.357 AC XY: 48351 AN XY: 135620

Gnomad AFR exome AF: 0.181

Gnomad AMR exome AF: 0.311

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.379

Gnomad SAS exome AF: 0.503

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.324

Gnomad OTH exome AF: 0.342

GnomAD4 exome AF: 0.336 AC: 491155 AN: 1461632 Hom.: 84626 Cov.: 45 AF XY: 0.341 AC XY: 248165 AN XY: 727128

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.314

Gnomad4 ASJ exome AF: 0.357

Gnomad4 EAS exome AF: 0.353

Gnomad4 SAS exome AF: 0.498

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.325

Gnomad4 OTH exome AF: 0.332

GnomAD4 genome AF: 0.299 AC: 45490 AN: 151976 Hom.: 7355 Cov.: 32 AF XY: 0.306 AC XY: 22737 AN XY: 74254

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.319

Gnomad4 ASJ AF: 0.349

Gnomad4 EAS AF: 0.368

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.403

Gnomad4 NFE AF: 0.330

Gnomad4 OTH AF: 0.324

Alfa AF: 0.325 Hom.: 14458

Bravo AF: 0.282

Asia WGS AF: 0.405 AC: 1408 AN: 3478

EpiCase AF: 0.321

EpiControl AF: 0.331

ClinVar

Significance: Benign

Submissions summary: Benign:30 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:10 Other:1

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 22, 2011	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
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 0.3304 (Asian), 0.128 (African), 0.3536 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	High frequency in a 1kG or ESP population: 32.4 %. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 02, 2016	p.Leu771Leu in exon 10 of BRCA1: This variant is not expected to have clinical s ignificance because it has been identified in 50% (8241/16498) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs16940). -

Hereditary breast ovarian cancer syndrome Benign:4

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	Dec 18, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	Apr 19, 2022	- -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 01, 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 31, 2015	- -

Familial cancer of breast Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2017	- -
not provided, no classification provided	literature only	Genomic Research Center, Shahid Beheshti University of Medical Sciences	-	- -

Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.2
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs16940; hg19: chr17-41245237; COSMIC: COSV58786443; COSMIC: COSV58786443;