17-43093454-C-T

Position:

• chr17-43093454-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 BP4_Strong BP6_Very_Strong BA1

The ENST00000357654.9(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. 14/20 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. D693I?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.057 (338 hom., cov: 32)
  • Exomes 𝑓: 0.071 (4107 hom.)
• Consequence: BRCA1 ENST00000357654.9 missense
• Clinical Significance: Benign reviewed by expert panel B:33 O:1
• Conservation: PhyloP100: 0.205

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 -18 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-43093454-C-TAT is described in ClinVar as [Pathogenic]. Clinvar id is 266212.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 id is 41808.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43093454-C-T is described in Lovd as [Benign]. Variant chr17-43093454-C-T is described in Lovd as [Pathogenic]. Variant chr17-43093454-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0749 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA1	NM_007294.4	c.2077G>A	p.Asp693Asn	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.2077G>A	p.Asp693Asn	missense_variant	10/23	1	NM_007294.4	ENSP00000350283	P4

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

GnomAD3 exomes AF: 0.0584 AC: 14674 AN: 251126 Hom.: 565 AF XY: 0.0596 AC XY: 8087 AN XY: 135712

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 SAS exome AF: 0.0354

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

Gnomad4 AFR exome AF: 0.0234

Gnomad4 AMR exome AF: 0.0360

Gnomad4 ASJ exome AF: 0.0922

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0359

Gnomad4 FIN exome AF: 0.0862

Gnomad4 NFE exome AF: 0.0782

Gnomad4 OTH exome AF: 0.0665

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

Gnomad4 AFR AF: 0.0230

Gnomad4 AMR AF: 0.0534

Gnomad4 ASJ AF: 0.0862

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0319

Gnomad4 FIN AF: 0.0960

Gnomad4 NFE AF: 0.0767

Gnomad4 OTH AF: 0.0601

Alfa AF: 0.0725 Hom.: 958

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:33 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
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, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Feb 20, 2004	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	High frequency in a 1kG or ESP population: 7.0 %. -
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 0.01016 (African), 0.08443 (European), derived from 1000 genomes (2012-04-30). -
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	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 17, 2011	- -

not specified Benign:7 Other:1

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
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	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 25, 2015	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 27, 2016	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 20, 2018	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 10, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 29, 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 05, 2014	- -

Hereditary breast ovarian cancer syndrome Benign:4

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	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 13, 2014	- -
Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -

Familial cancer of breast Benign:2

Benign, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 03, 2013	The variant is found in BRCA1-BRCA2 panel(s). -

BRCA1-related cancer predisposition Benign:1

Benign, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Oct 02, 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

Mar 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

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;.;.;.;T
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.81	T;T;T;T;T
MetaRNN	Benign	0.0017	T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N;N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.030	N;N;N;N;.
REVEL	Benign	0.13
Sift	Uncertain	0.012	D;D;D;D;.
Sift4G	Benign	0.18	T;T;T;D;.
Polyphen		0.0	B;.;.;B;.
Vest4		0.21
MPC		0.080
ClinPred		0.0054	T
GERP RS		1.2
Varity_R		0.046
gMVP		0.077

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: rs4986850; hg19: chr17-41245471; COSMIC: COSV58789708; COSMIC: COSV58789708;