rs28897724

Positions:

• chr13-32338423-G-A
• chr13-32338423-G-C
• chr13-32338423-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000059.4(BRCA2):​c.4068G>A​(p.Leu1356=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0034 in 1,608,220 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (6 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Benign reviewed by expert panel U:1 B:39
• Conservation: PhyloP100: -1.62

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 13-32338423-G-A is Benign according to our data. Variant chr13-32338423-G-A is described in ClinVar as [Benign]. Clinvar id is 51589.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338423-G-A is described in Lovd as [Benign]. Variant chr13-32338423-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 6 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.4068G>A	p.Leu1356=	synonymous_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.4068G>A	p.Leu1356=	synonymous_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00278 AC: 423 AN: 152116 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00367

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00416

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00299 AC: 736 AN: 246498 Hom.: 3 AF XY: 0.00292 AC XY: 389 AN XY: 133050

Gnomad AFR exome AF: 0.000372

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.00607

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000692

Gnomad FIN exome AF: 0.00195

Gnomad NFE exome AF: 0.00436

Gnomad OTH exome AF: 0.00400

GnomAD4 exome AF: 0.00347 AC: 5052 AN: 1455986 Hom.: 6 Cov.: 35 AF XY: 0.00341 AC XY: 2465 AN XY: 723676

Gnomad4 AFR exome AF: 0.000271

Gnomad4 AMR exome AF: 0.00361

Gnomad4 ASJ exome AF: 0.00659

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000832

Gnomad4 FIN exome AF: 0.00193

Gnomad4 NFE exome AF: 0.00398

Gnomad4 OTH exome AF: 0.00304

GnomAD4 genome AF: 0.00278 AC: 423 AN: 152234 Hom.: 1 Cov.: 33 AF XY: 0.00239 AC XY: 178 AN XY: 74438

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00366

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00416

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00399 Hom.: 1

Bravo AF: 0.00312

EpiCase AF: 0.00487

EpiControl AF: 0.00368

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:39

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:14

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Feb 25, 2016	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Department of Medical Genetics, University Hospital of North Norway	May 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Likely 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	Genetics and Molecular Pathology, SA Pathology	Feb 17, 2020	The BRCA2 c.4068G>A variant is classified as Benign (BA1) This BRCA2 c.4068G>A variant is synonymous (silent). The frequency of this variant in population databases is higher than expected for this disorder indicating this variant is a benign polymorphism (BA1). Population frequency of .29% for this variant greater than expected for pathogenic BRCA2 variants (expected to be 0.45% for all BRCA2 pathogenic variants). ENIGMA BRCA1/2 Classification Criteria (2017-06-29): benign -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 29, 2017	Synonymous substitution variant, with low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/) and frequency 0.0047 (Non-Finnish European), 0.0023 (Finnish), 0.0029 (Admixed American/Latino), derived from ExAC (2014-12-17). -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Feb 07, 2014	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 14, 2011	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 15, 2018	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 10, 2019	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 30, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 22, 2014	- -
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	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -

Hereditary cancer-predisposing syndrome Benign:5

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	May 03, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 15, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 15, 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. -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -

Hereditary breast ovarian cancer syndrome Benign:5

Benign, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Apr 25, 2016	- -
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	Nov 16, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 17, 2014	- -

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 17, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	BRCA2: BP4, BP7, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Aug 22, 2017	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 23, 2019

- -

Fanconi anemia complementation group D1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 15, 2018

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely 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.Leu1356Leu variant has been reported in the literature in 29/16512 proband chromosomes and 0/80 control chromosomes. However, an insufficient number of controls were typed to establish the variants' allele frequency in the general population (Edwards 2003, Haffty 2006, Infante 2006, Stagel 2011, Van der Hout 2006, Yang 2009). 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 and is reported in dbSNP (ID#:rs28897724) with a global allele frequency of 0.001 (1000 genomes) increasing the likelihood this variant is benign. In addition, this variant is reported by Myriad Genetics as benign as of Oct 2008 (personal communication). In summary, this variant meets our laboratories' criteria for a benign variant. -

Familial cancer of breast Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.26
DANN	Benign	0.52

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: rs28897724; hg19: chr13-32912560; COSMIC: COSV101204039;