17-43071077-T-C

Variant names:

• chr17-43071077-T-C
• rs1799966
• NM_007294.4:c.4837A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007294.4(BRCA1):​c.4837A>G​(p.Ser1613Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,613,902 control chromosomes in the GnomAD database, including 94,249 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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. S1613D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.32 (8007 hom., cov: 32)
  • Exomes 𝑓: 0.34 (86242 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel B:35 O:2
• Conservation: PhyloP100: -0.194
• Publications: 316 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Fanconi anemia, complementation group S

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• pancreatic cancer, susceptibility to, 4

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.0711293E-4).
• BP6: Variant 17-43071077-T-C is Benign according to our data. Variant chr17-43071077-T-C is described in ClinVar as Benign. ClinVar VariationId is 41827.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007294.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	NM_007294.4	MANE Select	c.4837A>G	p.Ser1613Gly	missense	Exon 15 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.4903A>G	p.Ser1635Gly	missense	Exon 16 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.4903A>G	p.Ser1635Gly	missense	Exon 16 of 24	NP_001394511.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA1	ENST00000357654.9	TSL:1 MANE Select	c.4837A>G	p.Ser1613Gly	missense	Exon 15 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.4900A>G	p.Ser1634Gly	missense	Exon 16 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.4837A>G	p.Ser1613Gly	missense	Exon 15 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48290 AN: 151926 Hom.: 8001 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.329

Gnomad ASJ AF: 0.362

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.493

Gnomad FIN AF: 0.404

Gnomad MID AF: 0.354

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.333

GnomAD2 exomes AF: 0.354 AC: 88974 AN: 251384 AF XY: 0.362

Gnomad AFR exome AF: 0.240

Gnomad AMR exome AF: 0.317

Gnomad ASJ exome AF: 0.374

Gnomad EAS exome AF: 0.380

Gnomad FIN exome AF: 0.403

Gnomad NFE exome AF: 0.326

Gnomad OTH exome AF: 0.348

GnomAD4 exome AF: 0.340 AC: 496800 AN: 1461858 Hom.: 86242 Cov.: 59 AF XY: 0.345 AC XY: 250799 AN XY: 727226

African (AFR) AF: 0.233 AC: 7805 AN: 33480

American (AMR) AF: 0.321 AC: 14344 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 9616 AN: 26136

East Asian (EAS) AF: 0.353 AC: 14028 AN: 39698

South Asian (SAS) AF: 0.499 AC: 43064 AN: 86256

European-Finnish (FIN) AF: 0.396 AC: 21175 AN: 53416

Middle Eastern (MID) AF: 0.373 AC: 2154 AN: 5768

European-Non Finnish (NFE) AF: 0.327 AC: 364076 AN: 1111986

Other (OTH) AF: 0.340 AC: 20538 AN: 60394

GnomAD4 genome AF: 0.318 AC: 48324 AN: 152044 Hom.: 8007 Cov.: 32 AF XY: 0.324 AC XY: 24084 AN XY: 74308

African (AFR) AF: 0.237 AC: 9828 AN: 41468

American (AMR) AF: 0.330 AC: 5029 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 1256 AN: 3468

East Asian (EAS) AF: 0.370 AC: 1917 AN: 5178

South Asian (SAS) AF: 0.492 AC: 2370 AN: 4816

European-Finnish (FIN) AF: 0.404 AC: 4268 AN: 10558

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22581 AN: 67976

Other (OTH) AF: 0.337 AC: 711 AN: 2112

Alfa AF: 0.325 Hom.: 29484

Bravo AF: 0.303

TwinsUK AF: 0.339 AC: 1258

ALSPAC AF: 0.337 AC: 1300

ESP6500AA AF: 0.243 AC: 1069

ESP6500EA AF: 0.327 AC: 2809

ExAC AF: 0.349 AC: 42424

Asia WGS AF: 0.411 AC: 1430 AN: 3478

EpiCase AF: 0.324

EpiControl AF: 0.333

ClinVar

Significance: Benign

Submissions summary: Benign:35 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

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

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breast Cancer Information Core (BIC) (BRCA1)

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

Mar 22, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 09, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 02, 2014

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

High frequency in a 1kG or ESP population: 32.7 %. This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Aug 10, 2015

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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 = 0.00000000000309. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.3322 (Asian), 0.2195 (African), 0.3615 (European), derived from 1000 genomes (2012-04-30).

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not specified Benign:8 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Ser1613Gly variant was identified extensively in the literature from individuals or families with hereditary breast and ovarian cancers, and also control chromosomes from healthy individuals (Shattuck-Eidens 1997, Tavtigian 2006, Tommasi 2008, Phelan 2005, McKean-Cowdin 2005, Johnson 2007, Ho-Gay 2000, Greenman 1998, Forat-Yazdi 2015, Diez 2003, Abkevich 2004, Carvalho 2007). Most of the studies have concluded the p.Ser1613Gly variant benign or a polymorphism. The variant was also identified in our laboratory and in dbSNP (ID: rs1799966) with benign/other allele; in the 1000 Genomes Project in 1782 of 5000 chromosomes (frequency: 0.3558); in HapMap-CEU in 151 of 220 chromosomes (frequency: 0.686363); HapMap-YRI in 187 of 226 chromosomes (frequency: 0.8274333); HapMap-MKK in 224 of 286 chromosomes (frequency: 0.78321677). In Exome Variant Server project the variant was identified in 2809 of 8600 (freq: 0.326627) European American and in 1069 of 4406 (freq: 0.2426) African American alleles. In the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) the variant was identified in 42424 of 121360 chromosomes, with 7852 homozygotes (frequency: 0.3496) from a population of South Asians, European (Non-Finnish), East Asian, African, Latino, European (Finnish) and other individuals. The variant was identified in GeneInsight COGR, Clinvar (8 of 10 submitters classified as benign), Clinvitae, COSMIC, BRCA Share-UMD (co-occurred with BRCA1 and BRCA2 pathogenic variants), BIC, ARUP, LOVD and Fanconi’s Anemia LOVD databases. The p.Ser1613 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Jan 07, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 01, 2017

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:4

Nov 28, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary breast ovarian cancer syndrome Benign:4

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 08, 2013

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:3

Jan 02, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 06, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Aug 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Familial cancer of breast Benign:2

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 23, 2017

Baylor Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1-related cancer predisposition Benign:1

Oct 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

May 06, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Malignant tumor of breast Benign:1

Center of Medical Genetics and Primary Health Care

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breast carcinoma Benign:1

Apr 03, 2019

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	6.9
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.00031	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.19
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.25
Sift	Benign	0.040	D
Sift4G	Benign	0.19	T
Polyphen		0.26	B
Vest4		0.30
MPC		0.076
ClinPred		0.0023	T
GERP RS		1.5
Varity_R		0.057
gMVP		0.23
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1799966; hg19: chr17-41223094; COSMIC: COSV58783381; COSMIC: COSV58783381;