rs1801426

chr13-32398747-A-G

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.10234A>G(p.Ile3412Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,613,938 control chromosomes in the GnomAD database, including 726 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I3412S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.036 (287 hom., cov: 32)
  • Exomes 𝑓: 0.0075 (439 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:40 O:1
• Conservation: PhyloP100: 0.556

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=0.0017527342).
• BP6: Variant 13-32398747-A-G is Benign according to our data. Variant chr13-32398747-A-G is described in ClinVar as [Benign]. Clinvar id is 41540.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32398747-A-G is described in Lovd as [Benign]. Variant chr13-32398747-A-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.104 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.10234A>G	p.Ile3412Val	missense_variant	27/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.10234A>G	p.Ile3412Val	missense_variant	27/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.0363 AC: 5525 AN: 152176 Hom.: 283 Cov.: 32

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0453

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00876

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.0320

GnomAD3 exomes AF: 0.0233 AC: 5843 AN: 250706 Hom.: 271 AF XY: 0.0180 AC XY: 2435 AN XY: 135584

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.0905

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0240

Gnomad SAS exome AF: 0.00219

Gnomad FIN exome AF: 0.00801

Gnomad NFE exome AF: 0.00153

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.00751 AC: 10984 AN: 1461644 Hom.: 439 Cov.: 31 AF XY: 0.00670 AC XY: 4869 AN XY: 727126

Gnomad4 AFR exome AF: 0.115

Gnomad4 AMR exome AF: 0.0843

Gnomad4 ASJ exome AF: 0.000612

Gnomad4 EAS exome AF: 0.0215

Gnomad4 SAS exome AF: 0.00233

Gnomad4 FIN exome AF: 0.00708

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0364 AC: 5536 AN: 152294 Hom.: 287 Cov.: 32 AF XY: 0.0366 AC XY: 2728 AN XY: 74470

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.0456

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0233

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.00876

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.0317

Alfa AF: 0.00762 Hom.: 78

Bravo AF: 0.0447

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.106 AC: 469

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.0223 AC: 2714

Asia WGS AF: 0.0250 AC: 89 AN: 3478

EpiCase AF: 0.00218

EpiControl AF: 0.00160

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:40 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:11

Benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 14, 2011	- -
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	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
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, 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 0.02972 (Asian), 0.126 (African), derived from 1000 genomes (2012-04-30). -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
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	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 05, 2013	- -

not specified Benign:10 Other:1

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
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	Eurofins Ntd Llc (ga)	Mar 19, 2015	- -
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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 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	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 15, 2020	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

Hereditary cancer-predisposing syndrome Benign:5

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 23, 2020	- -
Benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Mar 02, 2018	- -
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	clinical testing	Vantari Genetics	Jan 06, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 05, 2014	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 28, 2016	- -
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	Dec 19, 2016	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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	Jan 13, 2014	- -

Familial cancer of breast Benign:2

Benign, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 23, 2017	- -
Likely benign, no assertion criteria provided	literature only	Center for Precision Medicine, Meizhou People's Hospital	-	- -

Breast neoplasm Uncertain:1

Uncertain significance, criteria provided, single submitter

research

A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center

-

- -

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

May 17, 2022

- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jul 10, 2015

- -

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. -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Ile3412Val variant has been previously reported in the literature in 59 of 4707 (frequency of 0.006) probands with breast or esophageal cancer and was also identified in 33 of 5486 (frequency of 0.003) controls increasing the likelihood that this is a low frequency benign variant (Capanu_2011_21520273, Vehmanen_1997_ 9150152, Freedman_2004_15317758, Johnson_2007­_17341484, Bergthorsson_2001_11389159, Kuusisto_2011_­21356067, Palmieri_2002_12453858, Hu_2004_14647438). The variant was also identified in the LOVD (4X), UMD (30X), and BIC (111X) databases. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs1801426) with a global minor allele frequency (MAF) of 0.043 (1000 genomes), increasing the likelihood that this is a low frequency benign variant. The Ile3412 residue is not highly conserved in mammals and computational analyses (SIFT, AlignGVGD) do not predict any effect on the protein function. In the UMD database, this variant has been identified in three individuals with a second pathogenic variant with a breast or ovarian cancer phenotype, and also found co-occurring with a deleterious BRCA2 mutation 1493delA in a cell line derived from a primary breast cancer (Teng 1996), thereby increasing the likelihood that this variant does not have clinical significance. In addition, Myriad genetics has reported this variant as a polymorphism increasing the likelihood this variant is benign (personal communication). In summary, based on the above information, this variant is classified as benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.75
Cadd	Benign	0.47
Dann	Benign	0.49
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.019	N
MetaRNN	Benign	0.0018	T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.028
Sift	Benign	0.92	T;T
Sift4G	Benign	0.35	T;T
Vest4		0.020
MPC		0.020
ClinPred		0.00057	T
GERP RS		-0.29
gMVP		0.018

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: rs1801426; hg19: chr13-32972884; COSMIC: COSV58412412; COSMIC: COSV58412412;