rs799917

chr17-43092919-G-Achr17-43092919-G-Cchr17-43092919-G-T

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.2612C>T(p.Pro871Leu) variant causes a missense change. The variant allele was found at a frequency of 0.376 in 1,613,362 control chromosomes in the GnomAD database, including 124,333 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. P871L?) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.49 (21276 hom., cov: 32)
  • Exomes 𝑓: 0.36 (103057 hom.)
• Consequence: BRCA1 NM_007294.4 missense
• Clinical Significance: Benign reviewed by expert panel B:36 O:1
• Conservation: PhyloP100: 4.25

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 chr17-43092919-G-AA is described in ClinVar as [Pathogenic]. Clinvar id is 54620.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=9.915395E-7).
• BP6: Variant 17-43092919-G-A is Benign according to our data. Variant chr17-43092919-G-A is described in ClinVar as [Benign]. Clinvar id is 41812.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr17-43092919-G-A is described in Lovd as [Benign]. Variant chr17-43092919-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.803 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA1	NM_007294.4	c.2612C>T	p.Pro871Leu	missense_variant	10/23	ENST00000357654.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA1	ENST00000357654.9	c.2612C>T	p.Pro871Leu	missense_variant	10/23	1	NM_007294.4	P4

Frequencies

GnomAD3 genomes AF: 0.487 AC: 74015 AN: 151956 Hom.: 21221 Cov.: 32

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.364

Gnomad EAS AF: 0.371

Gnomad SAS AF: 0.524

Gnomad FIN AF: 0.407

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.459

GnomAD3 exomes AF: 0.404 AC: 101374 AN: 251034 Hom.: 22738 AF XY: 0.402 AC XY: 54484 AN XY: 135700

Gnomad AFR exome AF: 0.825

Gnomad AMR exome AF: 0.348

Gnomad ASJ exome AF: 0.377

Gnomad EAS exome AF: 0.379

Gnomad SAS exome AF: 0.532

Gnomad FIN exome AF: 0.404

Gnomad NFE exome AF: 0.334

Gnomad OTH exome AF: 0.378

GnomAD4 exome AF: 0.364 AC: 532630 AN: 1461288 Hom.: 103057 Cov.: 62 AF XY: 0.368 AC XY: 267321 AN XY: 726932

Gnomad4 AFR exome AF: 0.831

Gnomad4 AMR exome AF: 0.356

Gnomad4 ASJ exome AF: 0.371

Gnomad4 EAS exome AF: 0.353

Gnomad4 SAS exome AF: 0.528

Gnomad4 FIN exome AF: 0.397

Gnomad4 NFE exome AF: 0.335

Gnomad4 OTH exome AF: 0.389

GnomAD4 genome AF: 0.487 AC: 74125 AN: 152074 Hom.: 21276 Cov.: 32 AF XY: 0.488 AC XY: 36241 AN XY: 74336

Gnomad4 AFR AF: 0.811

Gnomad4 AMR AF: 0.390

Gnomad4 ASJ AF: 0.364

Gnomad4 EAS AF: 0.370

Gnomad4 SAS AF: 0.522

Gnomad4 FIN AF: 0.407

Gnomad4 NFE AF: 0.341

Gnomad4 OTH AF: 0.462

Alfa AF: 0.355 Hom.: 25841

Bravo AF: 0.497

TwinsUK AF: 0.347 AC: 1288

ALSPAC AF: 0.344 AC: 1324

ESP6500AA AF: 0.800 AC: 3525

ESP6500EA AF: 0.336 AC: 2889

ExAC AF: 0.410 AC: 49775

Asia WGS AF: 0.473 AC: 1644 AN: 3478

EpiCase AF: 0.333

EpiControl AF: 0.342

ClinVar

Significance: Benign

Submissions summary: Benign:36 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 1 Benign:14

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	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA1)	Jun 21, 1999	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	High frequency in a 1kG or ESP population: 33.6 %. -
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, 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), 0.1362 (African), 0.3654 (European), derived from 1000 genomes (2012-04-30). -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 22, 2011	- -
Benign, criteria provided, single submitter	clinical testing	IntelligeneCG	Aug 18, 2017	- -
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, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 07, 2016	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	#N/A -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 02, 2016	p.Pro871Leu in exon 10 of BRCA1: This variant is not expected to have clinical s ignificance because it has been identified in 82% (8522/10402) of African chromo somes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs799917}). -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -

not provided Benign:3

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	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 07, 2016	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 11, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 13, 2015	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

Benign, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2017	- -

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

- -

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	0.042
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	17
Dann	Benign	0.88
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.61	T;T;T;T
MetaRNN	Benign	9.9e-7	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-3.4	N;N;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	5.7	N;N;N;N
REVEL	Benign	0.14
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0	B;.;.;B
Vest4		0.31
MPC		0.082
ClinPred		0.0025	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.020
gMVP		0.084

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs799917; hg19: chr17-41244936; COSMIC: COSV58784386; COSMIC: COSV58784386;