17-43092418-T-C

Position:

• chr17-43092418-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007294.4(BRCA1):​c.3113A>G​(p.Glu1038Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 1,613,370 control chromosomes in the GnomAD database, including 92,638 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1038A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.30 (7403 hom., cov: 31)
  • Exomes 𝑓: 0.34 (85235 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel P:1 U:1 B:35 O:2
• Conservation: PhyloP100: -0.149

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.296269E-4).
• BP6: Variant 17-43092418-T-C is Benign according to our data. Variant chr17-43092418-T-C is described in ClinVar as [Benign]. Clinvar id is 41815.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092418-T-C is described in Lovd as [Benign]. Variant chr17-43092418-T-C is described in Lovd as [Pathogenic]. Variant chr17-43092418-T-C is described in Lovd as [Likely_benign].
• 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.3113A>G	p.Glu1038Gly	missense_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.3113A>G	p.Glu1038Gly	missense_variant	10/23	1	NM_007294.4	ENSP00000350283.3

Frequencies

GnomAD3 genomes AF: 0.300 AC: 45583 AN: 151792 Hom.: 7401 Cov.: 31

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: 0.342

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.320

GnomAD3 exomes AF: 0.348 AC: 87427 AN: 251032 Hom.: 16145 AF XY: 0.357 AC XY: 48493 AN XY: 135674

Gnomad AFR exome AF: 0.182

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: 0.403

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.343

GnomAD4 exome AF: 0.337 AC: 492920 AN: 1461460 Hom.: 85235 Cov.: 50 AF XY: 0.343 AC XY: 249016 AN XY: 727044

Gnomad4 AFR exome AF: 0.175

Gnomad4 AMR exome AF: 0.315

Gnomad4 ASJ exome AF: 0.357

Gnomad4 EAS exome AF: 0.353

Gnomad4 SAS exome AF: 0.499

Gnomad4 FIN exome AF: 0.396

Gnomad4 NFE exome AF: 0.327

Gnomad4 OTH exome AF: 0.334

GnomAD4 genome AF: 0.300 AC: 45589 AN: 151910 Hom.: 7403 Cov.: 31 AF XY: 0.307 AC XY: 22773 AN XY: 74240

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.319

Gnomad4 ASJ AF: 0.349

Gnomad4 EAS AF: 0.369

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.403

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.324

Alfa AF: 0.323 Hom.: 17951

Bravo AF: 0.283

TwinsUK AF: 0.339 AC: 1256

ALSPAC AF: 0.336 AC: 1294

ESP6500AA AF: 0.188 AC: 830

ESP6500EA AF: 0.325 AC: 2799

ExAC AF: 0.343 AC: 41615

Asia WGS AF: 0.405 AC: 1408 AN: 3474

EpiCase AF: 0.323

EpiControl AF: 0.332

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:35 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

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

not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Aug 10, 2015	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 = 0.00000000000204. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.3304 (Asian), 0.128 (African), 0.3575 (European), derived from 1000 genomes (2012-04-30). -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	High frequency in a 1kG or ESP population: 32.5 %. -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -

not specified Benign:8 Other:1

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 18, 2016	p.Glu1038Gly in exon 10 of BRCA1: This variant is not expected to have clinical significance because it has been identified in 34.3% (41604/121342) of all chrom osomes tested by the Exome Aggregation Consortium (ExAC, http://exac.broadinstit ute.org; dbSNP rs16941). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -

Familial cancer of breast Pathogenic:1 Uncertain:1 Benign:2

Uncertain significance, no assertion criteria provided	literature only	Center for Precision Medicine, Meizhou People's Hospital	-	- -
Benign, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2017	- -
Pathogenic, no assertion criteria provided	research	Department of Medical Laboratory Science, Faculty of Allied Health Sciences, University of Peradeniya	Oct 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
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 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	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 2013	- -
Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 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	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 04, 2014	- -

BRCA1-related cancer predisposition Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 03, 2024

- -

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

May 06, 2022

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Center of Medical Genetics and Primary Health Care

-

- -

Breast carcinoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Medical Genomics, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Faculty of Medicine Ramathibodi Hospital, Mahidol University

Apr 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.66	T;T;T;T
MetaRNN	Benign	0.00023	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;.;.
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-5.7	D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.028	D;D;D;D
Sift4G	Uncertain	0.028	D;D;D;D
Polyphen		0.94	P;.;.;B
Vest4		0.28
MPC		0.24
ClinPred		0.031	T
GERP RS		-0.97
Varity_R		0.13
gMVP		0.21

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: rs16941; hg19: chr17-41244435; COSMIC: COSV58786412; COSMIC: COSV58786412;