chr13-32339554-C-T

Position:

• chr13-32339554-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000059.4(BRCA2):​c.5199C>T​(p.Ser1733Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,607,272 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0050 (42 hom.)
• Consequence: BRCA2 NM_000059.4 synonymous
• Clinical Significance: Benign reviewed by expert panel B:36
• Conservation: PhyloP100: -0.989

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 13-32339554-C-T is Benign according to our data. Variant chr13-32339554-C-T is described in ClinVar as [Benign]. Clinvar id is 51813.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339554-C-T is described in Lovd as [Likely_benign]. Variant chr13-32339554-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.989 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00467 (711/152094) while in subpopulation NFE AF= 0.00693 (471/67970). AF 95% confidence interval is 0.00641. There are 8 homozygotes in gnomad4. There are 339 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 8 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5199C>T	p.Ser1733Ser	synonymous_variant	11/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.5199C>T	p.Ser1733Ser	synonymous_variant	11/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.4830C>T	p.Ser1610Ser	synonymous_variant	11/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5199C>T		non_coding_transcript_exon_variant	10/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00468 AC: 711 AN: 151976 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.000918

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00374

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.0101

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00693

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00451 AC: 1111 AN: 246572 Hom.: 4 AF XY: 0.00435 AC XY: 581 AN XY: 133474

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.00308

Gnomad ASJ exome AF: 0.00629

Gnomad EAS exome AF: 0.000548

Gnomad SAS exome AF: 0.000340

Gnomad FIN exome AF: 0.0104

Gnomad NFE exome AF: 0.00581

Gnomad OTH exome AF: 0.00568

GnomAD4 exome AF: 0.00503 AC: 7323 AN: 1455178 Hom.: 42 Cov.: 45 AF XY: 0.00507 AC XY: 3668 AN XY: 723876

Gnomad4 AFR exome AF: 0.000543

Gnomad4 AMR exome AF: 0.00291

Gnomad4 ASJ exome AF: 0.00698

Gnomad4 EAS exome AF: 0.000632

Gnomad4 SAS exome AF: 0.000565

Gnomad4 FIN exome AF: 0.0110

Gnomad4 NFE exome AF: 0.00550

Gnomad4 OTH exome AF: 0.00386

GnomAD4 genome AF: 0.00467 AC: 711 AN: 152094 Hom.: 8 Cov.: 33 AF XY: 0.00456 AC XY: 339 AN XY: 74346

Gnomad4 AFR AF: 0.000916

Gnomad4 AMR AF: 0.00374

Gnomad4 ASJ AF: 0.00720

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000831

Gnomad4 FIN AF: 0.0101

Gnomad4 NFE AF: 0.00693

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00564 Hom.: 4

Bravo AF: 0.00369

Asia WGS AF: 0.000578 AC: 2 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:36

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:11

Benign, no assertion criteria provided	clinical testing	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	-	- -
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	GeneDx	Oct 09, 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	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency	Apr 18, 2017	- -
Benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Ser1733Ser variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site; in addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant was identified in 76 of 12892 proband chromosomes (frequency: 0.006) from individuals or families with breast or ovarian cancer, or pancreatic carcinoma/melanoma-prone families (Balabas 2010, Bartsch 2009, Borg 2010, Schroeder 2010, Slater 2010, Stegel 2011, van der Hout 2006, Wagner 1999, Weber 2006, Yang 2009). The variant was also present in 5 of 310 control chromosomes (frequency: 0.016) from healthy individuals (Cvok 2008, Stegel 2011). The variant was identified in dbSNP (ID: rs28897734) with a minor allele frequency of 0.0016 (1000 Genomes Project), NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC) database, Clinvitae database, Fanconi Anemia Mutation Database (LOVD), COSMIC, the ClinVar database (classified as “benign” by six submitters and “likely benign” by two submitters), GeneInsight COGR database (submitted by three clinical laboratories, with classifications of benign, presumed benign, and unclassified), the BIC database (11X with no clinical importance), and the BRCA Share (UMD) database (95X with a neutral classification). In the BRCA Share database, 15 samples were listed with co-occurring pathogenic BRCA1 or BRCA2 variants, increasing the likelihood that the p.Ser1733Ser variant is not clinically significant. The variant was identified at polymorphic allelic frequencies in two HAPMAP populations listed in the variant’s dbSNP record: HAPMAP-TSI (Toscans in Italy) and HAPMAP-MEX (Mexican ancestry in Los Angeles). The variant is also found at a polymorphic frequency (72/6606 alleles, frequency 0.0109) in a population of European (Finnish) individuals identified in the Exome Aggregation Consortium (ExAC) database; one of these individuals was homozygous for the variant, and two individuals from a cohort of European (Non-Finnish) were also homozygotes, increasing the likelihood of this being a benign variant. In addition, Myriad classifies this variant as a polymorphism (personal communication). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Department of Pathology and Molecular Medicine, Queen's University	Apr 20, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 02, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 23, 2016	p.Ser1733Ser in exon 11 of BRCA2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 1.09% (72/6606) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs28897734). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 11, 2016	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:9

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	Breast Cancer Information Core (BIC) (BRCA2)	Jun 12, 2000	- -
Benign, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Jun 29, 2017	Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.0109 (Finnish), derived from ExAC (2014-12-17). -
Benign, criteria provided, single submitter	clinical testing	Michigan Medical Genetics Laboratories, University of Michigan	Nov 03, 2014	- -
Benign, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	Mar 14, 2011	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 20, 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. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 10, 2014	- -
Likely benign, criteria provided, single submitter	literature only	Counsyl	Apr 04, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	BRCA2: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 24, 2023	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 15, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 30, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 28, 2014	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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 06, 2015	- -

Hereditary breast ovarian cancer syndrome Benign:3

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	Jan 27, 2014	- -

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

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

Nov 11, 2016

- -

Fanconi anemia complementation group D1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 20, 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. -

Familial cancer of breast Benign:1

Benign, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.4
DANN	Benign	0.20

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: rs28897734; hg19: chr13-32913691; COSMIC: COSV66455665;