rs766173

Positions:

• chr13-32332343-A-C
• chr13-32332343-A-G
• chr13-32332343-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000059.4(BRCA2):​c.865A>C​(p.Asn289His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0418 in 1,598,150 control chromosomes in the GnomAD database, including 2,166 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N289D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.041 (218 hom., cov: 32)
  • Exomes 𝑓: 0.042 (1948 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel B:36 O:1
• Conservation: PhyloP100: 0.498

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015439987).
• BP6: Variant 13-32332343-A-C is Benign according to our data. Variant chr13-32332343-A-C is described in ClinVar as [Benign]. Clinvar id is 41567.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332343-A-C is described in Lovd as [Likely_benign]. Variant chr13-32332343-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.865A>C	p.Asn289His	missense_variant	10/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.865A>C	p.Asn289His	missense_variant	10/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0409 AC: 6221 AN: 152198 Hom.: 215 Cov.: 32

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.0263

Gnomad AMR AF: 0.0970

Gnomad ASJ AF: 0.0441

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.114

Gnomad FIN AF: 0.0148

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0344

Gnomad OTH AF: 0.0463

GnomAD3 exomes AF: 0.0521 AC: 12475 AN: 239502 Hom.: 527 AF XY: 0.0548 AC XY: 7094 AN XY: 129342

Gnomad AFR exome AF: 0.0222

Gnomad AMR exome AF: 0.0731

Gnomad ASJ exome AF: 0.0383

Gnomad EAS exome AF: 0.103

Gnomad SAS exome AF: 0.116

Gnomad FIN exome AF: 0.0154

Gnomad NFE exome AF: 0.0350

Gnomad OTH exome AF: 0.0495

GnomAD4 exome AF: 0.0419 AC: 60573 AN: 1445834 Hom.: 1948 Cov.: 30 AF XY: 0.0445 AC XY: 31960 AN XY: 719010

Gnomad4 AFR exome AF: 0.0205

Gnomad4 AMR exome AF: 0.0752

Gnomad4 ASJ exome AF: 0.0411

Gnomad4 EAS exome AF: 0.119

Gnomad4 SAS exome AF: 0.115

Gnomad4 FIN exome AF: 0.0151

Gnomad4 NFE exome AF: 0.0341

Gnomad4 OTH exome AF: 0.0456

GnomAD4 genome AF: 0.0410 AC: 6240 AN: 152316 Hom.: 218 Cov.: 32 AF XY: 0.0436 AC XY: 3248 AN XY: 74476

Gnomad4 AFR AF: 0.0213

Gnomad4 AMR AF: 0.0978

Gnomad4 ASJ AF: 0.0441

Gnomad4 EAS AF: 0.100

Gnomad4 SAS AF: 0.114

Gnomad4 FIN AF: 0.0148

Gnomad4 NFE AF: 0.0344

Gnomad4 OTH AF: 0.0482

Alfa AF: 0.0349 Hom.: 122

Bravo AF: 0.0423

TwinsUK AF: 0.0299 AC: 111

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.0202 AC: 89

ESP6500EA AF: 0.0368 AC: 316

ExAC AF: 0.0515 AC: 6246

Asia WGS AF: 0.110 AC: 380 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:36 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:12

Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jan 12, 2015	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.1049 (Asian), 0.01423 (African), 0.03694 (European), derived from 1000 genomes (2012-04-30). -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 15, 2011	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	High frequency in a 1kG or ESP population: 3.7 %. -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -
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	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
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	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 specified Benign:10 Other:1

Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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	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, no classification provided	reference population	ITMI	Sep 19, 2013	- -
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	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 30, 2015	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	#N/A -

Hereditary breast ovarian cancer syndrome Benign:4

Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
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	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 13, 2014	- -

not provided Benign:3

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	Mar 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 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	curation	Sema4, Sema4	Jan 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 04, 2014	- -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 28, 2022

- -

Fanconi anemia complementation group D1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

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 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Uncertain	0.99
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.10	N
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-0.87	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.086
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.046	D;D
Vest4		0.12
MPC		0.022
ClinPred		0.010	T
GERP RS		1.7
gMVP		0.12

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: rs766173; hg19: chr13-32906480; COSMIC: COSV66448377;