NM_000059.4:c.9016T>G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000059.4(BRCA2):c.9016T>G(p.Tyr3006Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y3006C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:3

Conservation

PhyloP100: 7.22

Publications

7 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: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 28 uncertain in NM_000059.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

PP5

Variant 13-32379812-T-G is Pathogenic according to our data. Variant chr13-32379812-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 38202.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.9016T>G	p.Tyr3006Asp	missense_variant	Exon 23 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.9016T>G	p.Tyr3006Asp	missense_variant	Exon 23 of 27	5	NM_000059.4	ENSP00000369497.3	P51587
BRCA2	ENST00000530893.7 link	c.8647T>G	p.Tyr2883Asp	missense_variant	Exon 23 of 27	1		ENSP00000499438.2	A0A590UJI7
BRCA2	ENST00000614259.2 link	n.*1074T>G		non_coding_transcript_exon_variant	Exon 22 of 26	2		ENSP00000506251.1	A0A7P0TAP7
BRCA2	ENST00000614259.2 link	n.*1074T>G		3_prime_UTR_variant	Exon 22 of 26	2		ENSP00000506251.1	A0A7P0TAP7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460052

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726464

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33418

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39650

South Asian (SAS)

AF:

0.00

AC:

AN:

86216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1110432

Other (OTH)

AF:

0.00

AC:

AN:

60324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000853

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Jan 24, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRCA2 c.9016T>G (p.Tyr3006Asp) variant has been reported in the published literature in an individual who underwent multigene panel testing (PMID: 31853058 (2020)), and has been reported in an individual with breast cancer (GeneDx, personal communications). Experimental studies have demonstrated this variant is damaging to BRCA2 protein function (PMID: 32444794 (2020), 33609447 (2021), 35736817 (2022)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as likely pathogenic. -

Mar 18, 2025

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: defective homology-directed repair activity and sensitivity to PARP inhibitors (PMID: 32377563, 32444794, 33609447, 35665744, 35736817); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 9244T>G; This variant is associated with the following publications: (PMID: 25722345, 32377563, 35736817, 33609447, 32444794, 29884841, 35665744, 28569743, 31911673, 31853058, 12228710) -

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Aug 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 3006 of the BRCA2 protein (p.Tyr3006Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with prostate cancer and breast cancer (internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 38202). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 32444794, 33609447). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Jun 27, 2024

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

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA2 c.9016T>G (p.Tyr3006Asp) results in a non-conservative amino acid change located in the BRCA2, OB2 domain (IPR048262) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250700 control chromosomes. c.9016T>G has been reported in the literature in a setting of multi-gene panel testing in at least one individual with personal or family history of cancer (e.g. Li_2020). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least two publications report experimental evidence evaluating an impact on protein function showing moderate disruption of BRCA2 function in HDR assay (e.g. Richardson_2021) and sensitivity to PARP inhibitors in vitro (e.g. Yamazawa_2023). ClinVar contains an entry for this variant (Variation ID: 38202). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Jan 24, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

May 06, 2024

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Y3006D variant (also known as c.9016T>G), located in coding exon 22 of the BRCA2 gene, results from a T to G substitution at nucleotide position 9016. The tyrosine at codon 3006 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration is non functional in multiple assays including a homology-directed, DNA repair assay and multiple drug sensitivity assays (Richardson ME et al. Am J Hum Genet, 2021 03;108:458-468; Ikegami M et al. Nat Commun, 2020 05;11:2573). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Ambry internal data; Yang H et al. Science, 2002 Sep;297:1837-48). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1

Oct 16, 2006

Sharing Clinical Reports Project (SCRP)

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Familial cancer of breast

Uncertain:1

Mar 21, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.99

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.88

D;D

MetaSVM

Uncertain

0.48

PhyloP100

7.2

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.6

D;D

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Vest4

0.79

MutPred

0.70

Loss of sheet (P = 0.0084);Loss of sheet (P = 0.0084);

MVP

0.94

MPC

0.19

ClinPred

0.99

GERP RS

5.7

gMVP

0.86

Mutation Taster

=38/62

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over