chr13-32370971-T-C

Variant names:

• chr13-32370971-T-C
• rs11571746
• NM_000059.4:c.8503T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1 BP4_Strong BP6_Very_Strong

The NM_000059.4(BRCA2):​c.8503T>C​(p.Ser2835Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,614,036 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 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. S2835S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: BRCA2 NM_000059.4 missense
• Clinical Significance: Benign reviewed by expert panel B:32 O:1
• Conservation: PhyloP100: -0.843
• Publications: 40 publications found

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 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 17 benign, 25 uncertain in NM_000059.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.006334573).
• BP6: Variant 13-32370971-T-C is Benign according to our data. Variant chr13-32370971-T-C is described in ClinVar as Benign. ClinVar VariationId is 52606.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.8503T>C	p.Ser2835Pro	missense	Exon 20 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.8503T>C	p.Ser2835Pro	missense	Exon 20 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.8503T>C	p.Ser2835Pro	missense	Exon 20 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.8503T>C	p.Ser2835Pro	missense	Exon 20 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.8503T>C	p.Ser2835Pro	missense	Exon 20 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.8134T>C	p.Ser2712Pro	missense	Exon 20 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152106 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00190

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000549 AC: 138 AN: 251178 AF XY: 0.000435

Gnomad AFR exome AF: 0.00671

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000969

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000224 AC: 327 AN: 1461812 Hom.: 1 Cov.: 31 AF XY: 0.000231 AC XY: 168 AN XY: 727208

African (AFR) AF: 0.00448 AC: 150 AN: 33480

American (AMR) AF: 0.000425 AC: 19 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53408

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0000989 AC: 110 AN: 1111968

Other (OTH) AF: 0.000613 AC: 37 AN: 60392

GnomAD4 genome AF: 0.00187 AC: 285 AN: 152224 Hom.: 1 Cov.: 32 AF XY: 0.00155 AC XY: 115 AN XY: 74424

African (AFR) AF: 0.00583 AC: 242 AN: 41530

American (AMR) AF: 0.00190 AC: 29 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68012

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000880 Hom.: 0

Bravo AF: 0.00220

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000725 AC: 88

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:32 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:8 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 28, 2014

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.

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 04, 2022

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.7% (77/10388) African chromosomes

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 16, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breast-ovarian cancer, familial, susceptibility to, 2 Benign:8

May 28, 2019

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 20, 2014

Counsyl

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Jun 18, 2019

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 = 0.000863

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: 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

The p.Ser2835Pro variant has been identified in 7 out of 7570 proband chromosomes (frequency 0.001) in individuals with cutaneous malignant melanoma, and breast and ovarian cancer phenotypes, and identified in 1 out of 5064 control chromosomes (frequency <0.001) (Casula 2006, Caux-Moncoutier 2011, Frackenthal 2012, Johnson 2007, Palomba 2009, Tazzite 2012, Malone 2000, Karchin 2008, Schoumacher 2001). It is listed in dbSNP database as coming from a “clinical source” (ID#: rs11571746) however no frequency information was provided. The variant is identified in the EVS server as a low frequency variant increasing the likelihood this variant does not have clinical significance. The p.Ser2835 is not conserved in mammals, and computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein, and the variant amino acid Proline (Pro) residue is present in cat, dog and zebrafish, suggesting this variant may not be functionally important. In the UMD database, this variant has been identified in 2 (out of 13) individuals with breast or ovarian cancers, where a second pathogenic BRCA1 mutation was also detected, further suggesting that this is a benign variant. In addition, it is presented 34 times in the BIC database as a variant with no clinical significance. In summary based on the information presented above this variant is classified as benign.

Oct 30, 2014

Pathway Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:4

Mar 31, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 05, 2018

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BRCA2: BP4

Hereditary cancer-predisposing syndrome Benign:3

Apr 24, 2015

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 08, 2020

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

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.

Hereditary breast ovarian cancer syndrome Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: 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

Sep 29, 2014

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breast and/or ovarian cancer Benign:2

Aug 29, 2022

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Apr 13, 2013

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Prostate cancer;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

Feb 07, 2022

Fulgent Genetics, Fulgent Genetics

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

Fanconi anemia complementation group D1 Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	9.2
DANN	Benign	0.90
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.092	N
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.0063	T
MetaSVM	Benign	-1.0	T
PhyloP100		-0.84
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.16
Sift	Benign	0.30	T
Sift4G	Benign	0.33	T
Vest4		0.30
MVP		0.72
MPC		0.028
ClinPred		0.00090	T
GERP RS		-5.8
gMVP		0.47
Mutation Taster		=91/9	polymorphism

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

Other links and lift over

dbSNP: rs11571746; hg19: chr13-32945108; COSMIC: COSV66452143;