rs28897749

Positions:

• chr13-32363384-G-A
• chr13-32363384-G-C

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.8182G>A​(p.Val2728Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00357 in 1,614,150 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (17 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel B:40 O:1
• Conservation: PhyloP100: 0.416

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 (MetaRNN=0.0068537593).
• BP6: Variant 13-32363384-G-A is Benign according to our data. Variant chr13-32363384-G-A is described in ClinVar as [Benign]. Clinvar id is 41565.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32363384-G-A is described in Lovd as [Benign]. Variant chr13-32363384-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8182G>A	p.Val2728Ile	missense_variant	18/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8182G>A	p.Val2728Ile	missense_variant	18/27	5	NM_000059.4	ENSP00000369497	A2

Frequencies

GnomAD3 genomes AF: 0.00230 AC: 350 AN: 152172 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00414

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00208 AC: 522 AN: 250884 Hom.: 2 AF XY: 0.00207 AC XY: 281 AN XY: 135682

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.00402

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00370 AC: 5408 AN: 1461860 Hom.: 17 Cov.: 31 AF XY: 0.00363 AC XY: 2639 AN XY: 727226

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00172

Gnomad4 NFE exome AF: 0.00465

Gnomad4 OTH exome AF: 0.00199

GnomAD4 genome AF: 0.00230 AC: 350 AN: 152290 Hom.: 1 Cov.: 32 AF XY: 0.00220 AC XY: 164 AN XY: 74468

Gnomad4 AFR AF: 0.000866

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.00415

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00337 Hom.: 1

Bravo AF: 0.00213

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00453 AC: 39

ExAC AF: 0.00203 AC: 247

EpiCase AF: 0.00398

EpiControl AF: 0.00373

ClinVar

Significance: Benign

Submissions summary: Benign:40 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

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

Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Jan 02, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Likely benign, no assertion criteria provided	literature only	Pathway Genomics	Jul 24, 2014	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 18, 2019	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000345 -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:7 Other:1

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	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 21, 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, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 10, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 15, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Likely benign, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BRCA2: BP4, BS2 -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -

Hereditary cancer-predisposing syndrome Benign:6

Benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Jan 22, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Jul 12, 2017	- -
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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Nov 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 02, 2022	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Sep 29, 2020	- -

Hereditary breast ovarian cancer syndrome Benign:4

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	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 24, 2014	- -
Benign, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Mar 11, 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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 02, 2021

- -

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 01, 2020

- -

Fanconi anemia complementation group D1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Breast neoplasm Benign:1

Likely benign, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

BRCA2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 19, 2021

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

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The p.Val2728Ile variant was identified in 26 of 7026 proband chromosomes (frequency: 0.004) from individuals or families with breast, prostate or melanoma cancers, and was present in 4 of 1852 control chromosomes (frequency: 0.002) from healthy individuals (Sinilnikova 1999, Diez 2003, Haffy 2006, Luedeke 2009, Capanu 2011, Kuusisto 2011, Stegel 2011). The variant was identified by our laboratory in 2 individuals with breast cancer. The variant was also identified in dbSNP (ID: rs28897749 “With Other, untested allele”, in NHLBI Exome Sequencing Project (Exome Variant Server) in 39 of 8600 European American and 4 of 4406 African American; in HAPMAP-CEU in 2 of 224 chromosomes (frequency: 0.009) and in HAPMAP-MEX in 3 of 98 chromosomes(frequency: 0.031). In Exome Aggregation Consortium (ExAC) database the variant is found in 216 of 66738 (I homozygote) European (Non-Finnish), 18 of 6614 European (Finnish), 10 of 10404 African, 2 of 11576 Latino and 1 in 908 in Other alleles, increasing the likelihood this could be a low frequency benign variant. The variant was not found in East Asian and South Asian. The variant was identified in LOVD (7x predicted neutral), the ClinVar database (classified as a Benign variant by Invitae (Jun26, 2015), GeneDx (Oct21, 2013), Emory Genetics (Feb10, 2014), Ambry Genetics (Nov19, 2014), Molecular Genetics Diagnostic-CHEO, BIC (May29, 2002) and as Likely Benign by Counsyl (Jan02, 2014), Pathway Genomics (Jul24, 2014), CSER-University of Washington (Jun01, 2014), Biesecker Lab ClinSeq Project (Jul13, 2012); no classification was provided by ITMI. The variant was reported in GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (2X, classified as “benign” by 2 clinical laboratories), the BIC database (92X with NO clinical importance), and UMD (95X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA2:c.1257delT (p.Cys419TrpfsX11), c.7230delT (p.Phe2410LeufsX59), c.6209_6212delAAAG (p.Glu2070ValfsX10), and BRCA1:c.5123C>A (p.Ala1708Glu), c.2308delT (p.Ser770HisfsX22), c.4065_4068delTCAA (p.Asn1355LysfsX10), c.5137delG (p.Val1713X), increasing the likelihood that the p.Val2728Ile variant does not have clinical significance. In addition, Myriad classifies this as a polymorphism (personal communication). The Val2728 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) do not predict any effect on the protein function. In addition, the variant amino acid Ile (isoleucine) is present in other mammals and lower organisms increasing the likelihood that this variant does not have clinical significance. Overrepresentation of this variant had conferred 2.3-fold increased risk for sporadic prostate cancer and a 6-fold increased risk for familial prostate cancers, however larger sample sizes and replication studies are necessary to clarify the role of the variant in prostate cancer (Luedeke 2009). The c.8182G>A variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, we lean towards a more benign role for this variant. This variant is classified as Benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	1.2
DANN	Benign	0.24
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.022	N
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.0069	T;T
MetaSVM	Benign	-0.79	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.030	N;N
REVEL	Uncertain	0.46
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Vest4		0.30
MVP		0.54
MPC		0.019
ClinPred		0.0019	T
GERP RS		-7.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.19

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: rs28897749; hg19: chr13-32937521; COSMIC: COSV99061740; COSMIC: COSV99061740;