17-43093454-C-T

Variant names:

• chr17-43093454-C-T
• rs4986850
• NM_007294.4:c.2077G>A

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.2077G>A​(p.Asp693Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0698 in 1,613,950 control chromosomes in the GnomAD database, including 4,445 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. D693E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.057 (338 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4107 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel B:34 O:1
• Conservation: PhyloP100: 0.205
• Publications: 148 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=0.0017115176).
• BP6: Variant 17-43093454-C-T is Benign according to our data. Variant chr17-43093454-C-T is described in ClinVar as Benign. ClinVar VariationId is 41808.Status of the report is reviewed_by_expert_panel, 3 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0749 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.2077G>A	p.Asp693Asn	missense	Exon 10 of 23	NP_009225.1
	BRCA1	NM_001407581.1		c.2077G>A	p.Asp693Asn	missense	Exon 10 of 24	NP_001394510.1
	BRCA1	NM_001407582.1		c.2077G>A	p.Asp693Asn	missense	Exon 10 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.2077G>A	p.Asp693Asn	missense	Exon 10 of 23	ENSP00000350283.3
	BRCA1	ENST00000471181.7	TSL:1	c.2077G>A	p.Asp693Asn	missense	Exon 10 of 24	ENSP00000418960.2
	BRCA1	ENST00000470026.6	TSL:1	c.2077G>A	p.Asp693Asn	missense	Exon 10 of 23	ENSP00000419274.2

Frequencies

GnomAD3 genomes AF: 0.0569 AC: 8658 AN: 152126 Hom.: 338 Cov.: 32

Gnomad AFR AF: 0.0231

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0536

Gnomad ASJ AF: 0.0862

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0323

Gnomad FIN AF: 0.0960

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0767

Gnomad OTH AF: 0.0608

GnomAD2 exomes AF: 0.0584 AC: 14674 AN: 251126 AF XY: 0.0596

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.0336

Gnomad ASJ exome AF: 0.0941

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0898

Gnomad NFE exome AF: 0.0772

Gnomad OTH exome AF: 0.0658

GnomAD4 exome AF: 0.0711 AC: 103938 AN: 1461706 Hom.: 4107 Cov.: 34 AF XY: 0.0697 AC XY: 50660 AN XY: 727150

African (AFR) AF: 0.0234 AC: 782 AN: 33480

American (AMR) AF: 0.0360 AC: 1609 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0922 AC: 2408 AN: 26130

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39688

South Asian (SAS) AF: 0.0359 AC: 3100 AN: 86240

European-Finnish (FIN) AF: 0.0862 AC: 4598 AN: 53364

Middle Eastern (MID) AF: 0.0742 AC: 428 AN: 5768

European-Non Finnish (NFE) AF: 0.0782 AC: 86992 AN: 1111924

Other (OTH) AF: 0.0665 AC: 4017 AN: 60392

GnomAD4 genome AF: 0.0568 AC: 8651 AN: 152244 Hom.: 338 Cov.: 32 AF XY: 0.0566 AC XY: 4215 AN XY: 74440

African (AFR) AF: 0.0230 AC: 954 AN: 41540

American (AMR) AF: 0.0534 AC: 817 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0862 AC: 299 AN: 3468

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5190

South Asian (SAS) AF: 0.0319 AC: 154 AN: 4830

European-Finnish (FIN) AF: 0.0960 AC: 1017 AN: 10598

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0767 AC: 5214 AN: 68004

Other (OTH) AF: 0.0601 AC: 127 AN: 2112

Alfa AF: 0.0685 Hom.: 1334

Bravo AF: 0.0536

TwinsUK AF: 0.0836 AC: 310

ALSPAC AF: 0.0890 AC: 343

ESP6500AA AF: 0.0232 AC: 102

ESP6500EA AF: 0.0702 AC: 604

ExAC AF: 0.0568 AC: 6894

Asia WGS AF: 0.0160 AC: 54 AN: 3478

EpiCase AF: 0.0778

EpiControl AF: 0.0835

ClinVar

Significance: Benign

Submissions summary: Benign:34 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA1)

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

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.

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

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control 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

Mar 17, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 = 0.00000000000204. Also class 1 based on frequency >1% in an outbred sampleset. Frequency 0.01016 (African), 0.08443 (European), derived from 1000 genomes (2012-04-30).

Jan 02, 2014

Counsyl

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: literature only

High frequency in a 1kG or ESP population: 7.0 %. 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.

not specified Benign:7 Other:1

Mar 25, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 BRCA1 p.Asp693Asn variant was identified in the literature and was also identified in dbSNP (ID: rs4986850) “With Benign ,untested allele”, with a minor allele frequency of 0.034 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, the ClinVar database (classified as a benign variant by the Sharing Clinical Reports Project, derived from Myriad reports, by Invitae, BIC, Counsy, GeneDX, Ambry Genetics and Biesecker Laboratory ), GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (1X, classified as “benign” by a clinical laboratory), the BIC database (64X with no clinical importance), and UMD (16X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (c.IVS22+5G>C (c.5406+5G>C); c.5503C>T (p.Arg1835X); c.3257T>G (p.Leu1086X) BRCA1 and c.6405_6409delCTTAA (p.Asn2135LysfsX3) BRCA2), increasing the likelihood that the p.Asp693Asn variant does not have clinical significance. This variant was also identified in the HAPMAP-CEU in 22 of 226 chromosomes (frequency: 0.097), HAPMAP-YRI in 2 of 226 chromosomes (frequency: 0.009), HAPMAP-MKK in 5 of 286 chromosomes (frequency: 0.017), Exome Variant Server project in 706 of 13004 European American and African American alleles, increasing the likelihood that this may be a low frequency benign variant in certain populations of origin.The p.Asp693 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. Furthermore, six studies call the variant as polymorphism, neutral or of little clinical significance (Abkevich 2004, Bodian 2014, Feliubadalo 2013, Johnston 2012, Lindor 2012, Tavtigian 2006). 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

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Nov 01, 2017

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:5

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: research

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1: BP4, BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Dec 27, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:4

Feb 20, 2018

True Health Diagnostics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 10, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

Oct 29, 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.

Nov 05, 2014

Color Diagnostics, LLC DBA Color Health

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

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

Nov 13, 2014

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast Benign:2

Sep 03, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is found in BRCA1-BRCA2 panel(s).

Feb 23, 2017

Baylor Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA1-related cancer predisposition Benign:1

Oct 02, 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

Mar 23, 2022

Fulgent Genetics, Fulgent Genetics

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	0.075
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	7.1
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.20
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.030	N
REVEL	Benign	0.13
Sift	Uncertain	0.012	D
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.21
MPC		0.080
ClinPred		0.0054	T
GERP RS		1.2
Varity_R		0.046
gMVP		0.077
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs4986850; hg19: chr17-41245471; COSMIC: COSV58789708; COSMIC: COSV58789708;