NM_000059.4:c.3904A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_000059.4(BRCA2):c.3904A>G(p.Thr1302Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000192 in 1,560,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign 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. T1302S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2O:1

Conservation

PhyloP100: -1.92

Publications

9 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_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10112628).

BP6

Variant 13-32338259-A-G is Benign according to our data. Variant chr13-32338259-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142030.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BRCA2	NM_000059.4	MANE Select	c.3904A>G	p.Thr1302Ala	missense	Exon 11 of 27	NP_000050.3
BRCA2	NM_001432077.1		c.3904A>G	p.Thr1302Ala	missense	Exon 11 of 27	NP_001419006.1
BRCA2	NM_001406720.1		c.3904A>G	p.Thr1302Ala	missense	Exon 11 of 27	NP_001393649.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.3904A>G	p.Thr1302Ala	missense	Exon 11 of 27	ENSP00000369497.3
BRCA2	ENST00000544455.6	TSL:1	c.3904A>G	p.Thr1302Ala	missense	Exon 11 of 27	ENSP00000439902.1
BRCA2	ENST00000530893.7	TSL:1	c.3535A>G	p.Thr1179Ala	missense	Exon 11 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000142

AC:

AN:

1408712

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

697714

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31118

American (AMR)

AF:

0.00

AC:

AN:

34758

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24240

East Asian (EAS)

AF:

0.00

AC:

AN:

38982

South Asian (SAS)

AF:

0.0000129

AC:

AN:

77618

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51810

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5442

European-Non Finnish (NFE)

AF:

9.20e-7

AC:

AN:

1086632

Other (OTH)

AF:

0.00

AC:

AN:

58112

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

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:

0.00000657

AC:

AN:

152230

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41472

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:2

Mar 23, 2023

University of Washington Department of Laboratory Medicine, University of Washington

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

Mar 15, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces threonine with alanine at codon 1302 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast and/or ovarian cancer and an individual affected with prostate cancer (26852015, 31214711). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 3/60466 cases and 2/53461 unaffected controls (OR= 1.326 (95%CI 0.222 to 7.938); p-value=1; Leiden Open Variation Database DB-ID BRCA2_006843) (PMID: 33471991). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

Jul 16, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

not provided

Uncertain:2

Jan 05, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Sep 24, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed in large population cohorts (Lek et al., 2016); Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Cao 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 4132A>G; This variant is associated with the following publications: (PMID: 28726806, 26852015, 30702160, 31131967, 31825140)

not specified

Uncertain:1

Jun 23, 2025

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA2 c.3904A>G (p.Thr1302Ala) results in a non-conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant was absent in 207858 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3904A>G has been observed in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Cao_2016, Yao_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 30702160, 26852015, 31837001, 35186721). ClinVar contains an entry for this variant (Variation ID: 142030). Based on the evidence outlined above, the variant was classified as uncertain significance.

Breast-ovarian cancer, familial, susceptibility to, 2

Uncertain:1

Feb 06, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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.

Hereditary breast ovarian cancer syndrome

Uncertain:1

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1302 of the BRCA2 protein (p.Thr1302Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 26852015). ClinVar contains an entry for this variant (Variation ID: 142030). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

BRCA2-related disorder

Other:1

GenomeConnect - Invitae Patient Insights Network

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

Variant classified as Uncertain significance and reported on 01-29-2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.030

(source)

DANN

Benign

0.87

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.061

M_CAP

Benign

0.023

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.96

PhyloP100

-1.9

PrimateAI

Benign

0.33

PROVEAN

Uncertain

-3.1

REVEL

Benign

0.19

Sift

Benign

0.13

Sift4G

Benign

0.43

Vest4

0.15

MutPred

0.28

Loss of disorder (P = 0.0781)

MVP

0.74

MPC

0.022

ClinPred

0.051

GERP RS

-3.6

gMVP

0.14

Mutation Taster

=62/38

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over