rs28897762

Variant names:

• chr13-32398623-G-A
• rs28897762
• NM_000059.4:c.10110G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32398623-G-A
• chr13-32398623-G-C
• chr13-32398623-G-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000059.4(BRCA2):​c.10110G>A​(p.Arg3370Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,614,080 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (9 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Benign reviewed by expert panel U:2 B:31
• Conservation: PhyloP100: 0.137

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 13-32398623-G-A is Benign according to our data. Variant chr13-32398623-G-A is described in ClinVar as [Benign]. Clinvar id is 51043.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32398623-G-A is described in Lovd as [Benign]. Variant chr13-32398623-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.137 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 9 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.10110G>A	p.Arg3370Arg	synonymous_variant	Exon 27 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.10110G>A	p.Arg3370Arg	synonymous_variant	Exon 27 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9741G>A	p.Arg3247Arg	synonymous_variant	Exon 27 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*2168G>A		non_coding_transcript_exon_variant	Exon 26 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*2168G>A		3_prime_UTR_variant	Exon 26 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00127 AC: 193 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00204

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00140 AC: 352 AN: 251248 Hom.: 0 AF XY: 0.00147 AC XY: 199 AN XY: 135788

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000723

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00178 AC: 2595 AN: 1461810 Hom.: 9 Cov.: 31 AF XY: 0.00181 AC XY: 1319 AN XY: 727202

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000850

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00216

Gnomad4 FIN exome AF: 0.00249

Gnomad4 NFE exome AF: 0.00186

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00127 AC: 193 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.00122 AC XY: 91 AN XY: 74454

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.00204

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00150 Hom.: 0

Bravo AF: 0.00107

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00202

EpiControl AF: 0.00142

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:31

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:9

May 25, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 18, 2017

Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 15, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

BRCA2, c.10110G>A, p.Arg3370Arg, Predicted Benign. This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located near a splice junction, is listed in dbSNP (rs28897762) from a clinical source with an average heterozygosity and standard error of 0.004+/-0.047, and was also detected, with similar frequencies, in various ethnic mutation screening studies without any information to assess the significance of this variant (Bergthorsson_2001_11389159, Campos_2001_11843247, Diez_2003_12955716, Edwards_2003_12474142, Claes_2004_15026808, Infante_2006_16758124, Borg_2010_20104584, Stegel_2011_21232165). In addition, this variant is listed in the UMD mutation database to co-occur with a pathogenic mutation in BRCA1 (c.5330T>A/p.Tyr1769X), increasing the likelihood that p.Arg3370Arg is benign. Further, Myriad calls this a polymorphism (personal communication). In summary, based on the above information, the p.Arg3370Arg variant is predicted to be benign. -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 16, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:7

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 12, 2000

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 29, 2017

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.002 (Non-Finnish European), 0.0018 (Finnish), 0.0014 (South Asian), derived from ExAC (2014-12-17). -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2014

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Benign:5

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2021

Genetics Program, Instituto Nacional de Cancer

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

- -

Nov 16, 2021

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 27, 2014

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:4

Oct 16, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Jun 27, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Apr 13, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 10, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Benign:3

May 15, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: BP4, BP7 -

Fanconi anemia complementation group D1 Uncertain:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Breast and/or ovarian cancer Benign:1

Apr 14, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Benign:1

May 22, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Familial cancer of breast Benign:1

Feb 23, 2017

Baylor Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.84
DANN	Benign	0.63

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: rs28897762; hg19: chr13-32972760; COSMIC: COSV104700964; COSMIC: COSV104700964;