17-43071077-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5 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. 15/20 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. S1613A?) has been classified as Pathogenic.

• 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:34 O:2
• Conservation: PhyloP100: -0.194

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 chr17-43071076-CT-GGC is described in ClinVar as [Pathogenic]. Clinvar id is 180697.Status of the report is reviewed_by_expert_panel, 3 stars.
• 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 id is 41827.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43071077-T-C is described in Lovd as [Likely_benign]. Variant chr17-43071077-T-C is described in Lovd as [Benign]. Variant chr17-43071077-T-C is described in Lovd as [Pathogenic].
• 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	UniProt
BRCA1	NM_007294.4	c.4837A>G	p.Ser1613Gly	missense_variant	15/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.4837A>G	p.Ser1613Gly	missense_variant	15/23	1	NM_007294.4	P4

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

GnomAD3 exomes AF: 0.354 AC: 88974 AN: 251384 Hom.: 16559 AF XY: 0.362 AC XY: 49183 AN XY: 135858

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 SAS exome AF: 0.504

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

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.321

Gnomad4 ASJ exome AF: 0.368

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: 0.340

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

Gnomad4 AFR AF: 0.237

Gnomad4 AMR AF: 0.330

Gnomad4 ASJ AF: 0.362

Gnomad4 EAS AF: 0.370

Gnomad4 SAS AF: 0.492

Gnomad4 FIN AF: 0.404

Gnomad4 NFE AF: 0.332

Gnomad4 OTH AF: 0.337

Alfa AF: 0.327 Hom.: 14702

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:34 Other:2

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:11 Other:1

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
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 = 0.00000000000309. 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). -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 22, 2011	- -
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: 32.7 %. -
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. -
not provided, no classification provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	-	- -
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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -

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	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	Eurofins Ntd Llc (ga)	Jan 07, 2016	- -
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	-	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. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Hereditary breast ovarian cancer syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	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	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	Oct 08, 2013	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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	Nov 28, 2016	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 19, 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	Jan 02, 2022	- -

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	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -

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 03, 2019

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.91
FATHMM_MKL	Benign	0.031	N
LIST_S2	Benign	0.59	T;T;T;T;T;T;T;T;T;T
MetaRNN	Benign	0.00031	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-2.1	N;N;.;N;.;N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.040	D;D;.;T;.;D;D;D;D;D
Sift4G	Benign	0.19	T;D;T;T;T;D;T;.;.;T
Polyphen		0.26, 0.0020	.;B;.;.;.;.;.;.;B;.
Vest4		0.30
MPC		0.076
ClinPred		0.0023	T
GERP RS		1.5
Varity_R		0.057
gMVP		0.23

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