13-32339553-C-T

Variant names:

• chr13-32339553-C-T
• rs55639415
• NM_000059.4:c.5198C>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.5198C>T​(p.Ser1733Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00028 in 1,607,336 control chromosomes in the GnomAD database, including 2 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. S1733S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00070 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00024 (2 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel U:4 B:29
• Conservation: PhyloP100: 0.540

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=0.011440545).
• BP6: Variant 13-32339553-C-T is Benign according to our data. Variant chr13-32339553-C-T is described in ClinVar as [Benign]. Clinvar id is 37950.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339553-C-T is described in Lovd as [Benign]. Variant chr13-32339553-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.5198C>T	p.Ser1733Phe	missense_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.5198C>T	p.Ser1733Phe	missense_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.4829C>T	p.Ser1610Phe	missense_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.5198C>T		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.000684 AC: 104 AN: 152044 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000426 AC: 105 AN: 246462 Hom.: 0 AF XY: 0.000472 AC XY: 63 AN XY: 133420

Gnomad AFR exome AF: 0.00234

Gnomad AMR exome AF: 0.0000888

Gnomad ASJ exome AF: 0.00102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000536

Gnomad OTH exome AF: 0.000502

GnomAD4 exome AF: 0.000236 AC: 344 AN: 1455174 Hom.: 2 Cov.: 44 AF XY: 0.000268 AC XY: 194 AN XY: 723888

Gnomad4 AFR exome AF: 0.00392

Gnomad4 AMR exome AF: 0.0000911

Gnomad4 ASJ exome AF: 0.00158

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00133

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000549

GnomAD4 genome AF: 0.000697 AC: 106 AN: 152162 Hom.: 0 Cov.: 33 AF XY: 0.000753 AC XY: 56 AN XY: 74396

Gnomad4 AFR AF: 0.00214

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000237 Hom.: 0

Bravo AF: 0.000865

ESP6500AA AF: 0.00296 AC: 13

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000470 AC: 57

Asia WGS AF: 0.000289 AC: 1 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Uncertain:4 Benign:29

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1 Benign:6

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 21, 2016

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2015

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

Significance: Benign

Review Status: reviewed by expert panel

Collection Method: curation

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 = 0.000000000153 -

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 28, 2014

Counsyl

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

Feb 11, 2008

Sharing Clinical Reports Project (SCRP)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not provided Uncertain:2 Benign:4

-

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: BP4 -

Mar 12, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 29, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 13, 2012

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

not specified Benign:6

Mar 13, 2017

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

- -

Jun 02, 2017

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 19, 2017

Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1,BP4, BP6; This alteration has an allele frequency that is greater than expected for the associated disease, is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). -

Hereditary cancer-predisposing syndrome Benign:4

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 16, 2018

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 24, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 11, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Hereditary breast ovarian cancer syndrome Benign:3

Sep 27, 2021

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 19, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group D1 Uncertain:1

Jan 13, 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. -

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

Mar 22, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breast and/or ovarian cancer Benign:1

May 01, 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 cancer predisposition Benign:1

Sep 24, 2024

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Benign:1

Feb 17, 2020

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). -

Malignant tumor of breast Benign:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The p.Ser1733Phe variant has been reported in the literature in 1 of 1410 proband chromosomes (f=0.001) of young women with contralateral breast cancer, and in no chromosomes of young women with unilateral breast cancer chromosomes in this study (n=2796) (Borg 2010). In literature, it is also considered a “well-documented missense polymorphism” (Hearle 2003) with high odds in favour of neutrality (Easton 2007). This variant has been observed in the UMD (4x) database as a neutral polymorphism, and is listed in the CNPHI database with ACMG category 5. It is also listed in dbSNP (ID# rs55639415) as a single nucleotide variation with a minor allele frequency of 0.002 having been observed in 4 chromosomes (1000 Genomes). This variant has been reported in the EVS with a minor allele frequency of 0.001. This residue is conserved in mammals; however, computational analyses (PolyPhen, SIFT, AlignGVGD, BLOSUM) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. In summary, based on the above information, this variant is classified as Benign. -

Familial cancer of breast Benign:1

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Uncertain	0.98
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.069	N
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.011	T;T
MetaSVM	Benign	-0.95	T
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Benign	0.16
Sift	Uncertain	0.024	D;D
Sift4G	Uncertain	0.022	D;D
Vest4		0.51
MVP		0.85
MPC		0.029
ClinPred		0.0069	T
GERP RS		2.5
gMVP		0.23

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: rs55639415; hg19: chr13-32913690;