rs144848

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000059.4(BRCA2):c.1114A>C(p.Asn372His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.277 in 1,613,510 control chromosomes in the GnomAD database, including 63,594 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

Frequency

Genomes: 𝑓 0.24 ( 4773 hom., cov: 32)

Exomes 𝑓: 0.28 ( 58821 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:2B:36O:1

Conservation

PhyloP100: 0.320

Variant links:

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]

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005027443).

BP6

Variant 13-32332592-A-C is Benign according to our data. Variant chr13-32332592-A-C is described in ClinVar as [Benign]. Clinvar id is 9329.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332592-A-C is described in Lovd as [Likely_benign]. Variant chr13-32332592-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.344 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.1114A>C	p.Asn372His	missense_variant	10/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.1114A>C	p.Asn372His	missense_variant	10/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes

AF:

0.238

AC:

36156

AN:

151966

Hom.:

4768

Cov.:

show subpopulations

Gnomad AFR

AF:

0.125

Gnomad AMI

AF:

0.295

Gnomad AMR

AF:

0.304

Gnomad ASJ

AF:

0.360

Gnomad EAS

AF:

0.258

Gnomad SAS

AF:

0.356

Gnomad FIN

AF:

0.221

Gnomad MID

AF:

0.261

Gnomad NFE

AF:

0.276

Gnomad OTH

AF:

0.261

GnomAD3 exomes

AF:

0.280

AC:

69869

AN:

249852

Hom.:

10214

AF XY:

0.285

AC XY:

38560

AN XY:

135500

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.304

Gnomad ASJ exome

AF:

0.356

Gnomad EAS exome

AF:

0.267

Gnomad SAS exome

AF:

0.352

Gnomad FIN exome

AF:

0.230

Gnomad NFE exome

AF:

0.279

Gnomad OTH exome

AF:

0.282

GnomAD4 exome

AF:

0.281

AC:

409992

AN:

1461426

Hom.:

58821

Cov.:

AF XY:

0.283

AC XY:

205796

AN XY:

726994

show subpopulations

Gnomad4 AFR exome

AF:

0.125

Gnomad4 AMR exome

AF:

0.302

Gnomad4 ASJ exome

AF:

0.353

Gnomad4 EAS exome

AF:

0.236

Gnomad4 SAS exome

AF:

0.349

Gnomad4 FIN exome

AF:

0.232

Gnomad4 NFE exome

AF:

0.281

Gnomad4 OTH exome

AF:

0.276

GnomAD4 genome

AF:

0.238

AC:

36183

AN:

152084

Hom.:

4773

Cov.:

AF XY:

0.239

AC XY:

17733

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.125

Gnomad4 AMR

AF:

0.304

Gnomad4 ASJ

AF:

0.360

Gnomad4 EAS

AF:

0.258

Gnomad4 SAS

AF:

0.358

Gnomad4 FIN

AF:

0.221

Gnomad4 NFE

AF:

0.276

Gnomad4 OTH

AF:

0.267

Alfa

AF:

0.278

Hom.:

14900

Bravo

AF:

0.238

TwinsUK

AF:

0.282

AC:

1046

ALSPAC

AF:

0.284

AC:

1096

ESP6500AA

AF:

0.129

AC:

558

ESP6500EA

AF:

0.286

AC:

2449

ExAC

AF:

0.277

AC:

33603

Asia WGS

AF:

0.339

AC:

1177

AN:

3478

EpiCase

AF:

0.278

EpiControl

AF:

0.281

ClinVar

Significance: Benign

Submissions summary: Uncertain:2Benign:36Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1Benign:12

Uncertain significance, no assertion criteria provided	literature only	OMIM	Feb 01, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
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 0.2552 (Asian), 0.09756 (African), 0.2876 (European), derived from 1000 genomes (2012-04-30). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	High frequency in a 1kG or ESP population: 28.6 %. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
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	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited	-	- -

not specified

Benign:8Other:1

Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
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	May 23, 2016	p.Asn372His in exon 10 of BRCA2: This variant is not expected to have clinical s ignificance because it has been identified in 35.58% (5867/16490) of South Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitu te.org; dbSNP rs144848). -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 23, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneKor MSA	Nov 01, 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	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:5

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	Nov 28, 2016	- -
Benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 32846166, 25348552, 21476145, 24289560, 32356124, 31477031, 29988080, 21990134, 24728327, 26306726, 27153395, 11062481, 19253839, 18288416, 22044372, 24323938, 23249957, 14555511, 15695382, 21702907, 17767707, 21952622, 20352487, 20135345, 22703879) -

Hereditary breast ovarian cancer syndrome

Benign:4

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 23, 2014	- -
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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -

Hereditary cancer-predisposing syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 07, 2019	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 17, 2020	- -

Breast ductal adenocarcinoma

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Next Generation Diagnostics, Novartis Institutes for BioMedical Research, Inc.

Jul 20, 2015

- -

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 29, 2022

- -

Fanconi anemia complementation group D1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

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

0.070

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

DANN

Benign

0.93

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.087

MetaRNN

Benign

0.0050

T;T

MetaSVM

Benign

-0.95

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.60

N;N

REVEL

Benign

0.041

Sift

Benign

0.14

T;T

Sift4G

Benign

0.34

T;T

Vest4

0.081

MPC

0.021

ClinPred

0.0012

GERP RS

0.40

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

gMVP

0.054

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over