rs41293521

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PM1BP4_StrongBP6_Very_Strong

The NM_000059.4(BRCA2):c.9292T>C(p.Tyr3098His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000225 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y3098C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:3B:21O:1

Conservation

PhyloP100: 0.618

Publications

34 publications found

Variant links:

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

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 14 benign, 17 uncertain in NM_000059.4

BP4

Computational evidence support a benign effect (MetaRNN=0.032249957).

BP6

Variant 13-32394724-T-C is Benign according to our data. Variant chr13-32394724-T-C is described in ClinVar as Benign. ClinVar VariationId is 38227.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.9292T>C	p.Tyr3098His	missense_variant	Exon 25 of 27	ENST00000380152.8	NP_000050.3	P51587

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
BRCA2	ENST00000380152.8 link	c.9292T>C	p.Tyr3098His	missense_variant	Exon 25 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.8923T>C	p.Tyr2975His	missense_variant	Exon 25 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*1350T>C		non_coding_transcript_exon_variant	Exon 24 of 26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259.2 link	n.*1350T>C		3_prime_UTR_variant	Exon 24 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000916

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000291

AC:

AN:

250874

AF XY:

0.000251

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00101

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000291

Gnomad OTH exome

AF:

0.000654

GnomAD4 exome

AF:

0.000221

AC:

323

AN:

1461540

Hom.:

Cov.:

AF XY:

0.000206

AC XY:

150

AN XY:

727056

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33474

American (AMR)

AF:

0.00103

AC:

AN:

44694

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.00

AC:

AN:

86210

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000228

AC:

253

AN:

1111808

Other (OTH)

AF:

0.000315

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000263

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74514

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41578

American (AMR)

AF:

0.000915

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000279

AC:

AN:

68036

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000236

Hom.:

Bravo

AF:

0.000446

ExAC

AF:

0.000255

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:21Other:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:2Benign:7

Sep 05, 2008

Sharing Clinical Reports Project (SCRP)

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 21, 2015

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

Significance: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 = 0.00000349 -

Nov 03, 2014

Michigan Medical Genetics Laboratories, University of Michigan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 07, 2015

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 24, 2015

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 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. -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1Benign:5Other:1

Dec 07, 2021

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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:Uncertain significance

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: Has been reported in 2 families with female breast and ovarian cancer (Serova-Sinilnikova 1997). Has been classified as benign by Akbari 2011 (based on Myriad classification criteria), Bodian 2011 (presence in controls), Guidugli 2014 (functional assay), Lindor 2012 (posterior probability model OR). No functional impact in DNA break repair assay (Guidugli 2013). B/LB by SCRP, GeneDx, Ambry, Counsyl, Invitae; VUS by BIC in ClinVar. -

Jan 10, 2018

GeneDx

Significance:Likely 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. -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:3

Mar 11, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

Nov 29, 2020

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

not provided

Benign:2

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BRCA2: BP4, BS1, BS3 -

Jun 05, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breast and/or ovarian cancer

Benign:1

Apr 13, 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 23, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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 BRCA2, p.Tyr3098His variant was identified in 6 of 5110 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian and prostate cancer (Borg 2010, Edwards 2003, Gayther 1999, Serova-Sinilnikova 1997). The variant was also identified in dbSNP (ID: rs41293521) as â€šÃ„Ãºotherâ€šÃ„Ã¹, Clinvitae database (classified as benign by ClinVar and Invitae; uncertain significance by ClinVar), ARUP Laboratories BRCA Mutations Database (classified as not pathogenic), the ClinVar database (classified as benign by ENIGMA, MMGLUM, Invitae, Ambry Genetics, SCRP; likely benign by CHEO, GeneDx, Consyl; uncertain significance by BIC), GeneInsight COGR database (classified as benign, likely benign or uncertain significance by a clinical laboratories), the BIC database (33x with unknown clinical importance). This variant was identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004), the Exome Aggregation Consortium database (August 8th 2016) in 31 of 117284 chromosomes (freq. 0.0003) in the following populations: Latino in 15 of 11252 chromosomes (freq. 0.001), European in 15 of 93796 chromosomes (freq. 0.0002), African in 1 of 10290 chromosomes (freq. 0.0001), but was not seen in Asian, Finnish and other populations. In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (c.3841C>T (p.Gln1281X), c.1953dup (p.Lys652GlufsX21); c.6405_6409delCTTAA (p.Asn2135LysfsX3)), increasing the likelihood that the p.Tyr3098His variant does not have clinical significance. The variant was also identified by our laboratory in two individuals with breast cancer. The p.Tyr3098 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The 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 addition, several functional studies classified this variant as class 1 (IARC) with probability of being deleterious 1.07âˆšÃ³10â€šÃ Ã5 (Guidugli 2013, Lindor 2012). In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign. -

Hereditary breast ovarian cancer syndrome

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

0.059

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Uncertain

-0.070

CADD

Benign

(source)

DANN

Benign

0.13

Eigen

Benign

-1.2

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.051

M_CAP

Benign

0.045

MetaRNN

Benign

0.032

T;T

MetaSVM

Benign

-0.95

PhyloP100

0.62

PrimateAI

Benign

0.35

PROVEAN

Benign

0.39

N;N

REVEL

Uncertain

0.45

Sift

Benign

0.78

T;T

Sift4G

Benign

1.0

T;T

Vest4

0.35

MVP

0.76

MPC

0.022

ClinPred

0.0033

GERP RS

1.6

gMVP

0.36

Mutation Taster

=88/12

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over