chr13-32380135-GA-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000059.4(BRCA2):c.9253delA(p.Thr3085GlnfsTer19) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000658 in 151,972 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T3085T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

BRCA2
NM_000059.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 4.00

Publications

40 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: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-32380135-GA-G is Pathogenic according to our data. Variant chr13-32380135-GA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 52785.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.9253delA	p.Thr3085GlnfsTer19	frameshift_variant	Exon 24 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
BRCA2	ENST00000380152.8 link	c.9253delA	p.Thr3085GlnfsTer19	frameshift_variant	Exon 24 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7 link	c.8884delA	p.Thr2962GlnfsTer19	frameshift_variant	Exon 24 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2 link	n.*1311delA		non_coding_transcript_exon_variant	Exon 23 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2 link	n.*1311delA		3_prime_UTR_variant	Exon 23 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151972

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1458716

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725646

African (AFR)

AF:

0.00

AC:

AN:

33142

American (AMR)

AF:

0.00

AC:

AN:

43870

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26030

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.00

AC:

AN:

85620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111030

Other (OTH)

AF:

0.00

AC:

AN:

60236

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151972

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74222

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000242

AC:

AN:

41364

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10556

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67990

Other (OTH)

AF:

0.00

AC:

AN:

2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:4

May 30, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 18, 2016

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

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

Variant allele predicted to encode a truncated non-functional protein. -

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 08, 2020

Center of Medical Genetics and Primary Health Care

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

The BRCA2 variant p.Thr3085Glnfs is a known pathogenic variant in exon 23 in the Nucleic acid-binding OB-fold (T2968-3184L aa) domain and in a mutation hotspot of 16 pathogenic variants (PM1 Pathogenic Moderate). This frameshift variant disrupts the function of the domain (PVS1 Pathogenic Very Strong). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). 1 pathogenic prediction from GERP versus no benign predictions supports its deleterious effect (PP3 Pathogenic Supporting). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000324753.1) (PP5 Pathogenic Supporting). In our study the variant p.Thr3085Glnfs was found in a 41-year-old female with unilateral breast cancer with a family history of cancer. -

not provided

Pathogenic:3

Apr 20, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Identified in multiple individuals with a personal or family history of breast cancer (Malone 2006, Kim 2012, Son 2012, Ou 2013, Kang 2015, Kim 2016, Park 2017); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9481delA; This variant is associated with the following publications: (PMID: 22382806, 23593081, 26187060, 25863477, 22798144, 26848529, 16912212, 28205045, 28111427, 30787465, 30014164, 30702160, 33558524, 31825140) -

Aug 25, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The BRCA2 c.9253del (p.Thr3085Glnfs*19) variant has been reported in the published literature in individuals and families affected with breast cancer (PMIDs: 23593081 (2013), 25863477 (2015), 28205045 (2017), 37239058 (2023)) and prostate cancer (PMID: 37118955 (2023)). The frequency of this variant in the general population, 0.0000066 (1/151972 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Apr 25, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM2, PP4, PP5 -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Aug 11, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.9253delA pathogenic mutation, located in coding exon 23 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 9253, causing a translational frameshift with a predicted alternate stop codon (p.T3085Qfs*19). This mutation has been reported in several Korean breast cancer patients (Son BH et al. Breast Cancer Res. Treat. 2012 Jun;133:1143-52; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Park B et al. Breast Cancer Res. Treat. 2017 May;163(1):139-150). Another study identified this mutation in one Kazakh Chinese individual in a cohort of 32 Chinese breast cancer patients diagnosed at age 35 or younger (Ou J et al. J Breast Cancer 2013 Mar;16:50-4). Of note, this alteration is also designated as 9481delA in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Mar 04, 2025

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant deletes 1 nucleotide in exon 24 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 9481delA according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 6 individuals affected with breast cancer (PMID: 22382806, 23593081, 25863477, 28205045, 36980780, 37239058). This variant also has been detected in a breast cancer case-control meta-analysis in 4/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000919). A multifactorial analysis has reported a likelihood ratio for pathogenicity based on personal and family history of 4.092 from log(LR)=0.611947417 for two carriers (PMID: 31853058). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -

Feb 11, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1, PM5_Strong c.9253del, located in exon 24 of the BRCA2 gene, consists in the deletion of 1 nucleotide, causing a translational frameshift with a predicted alternate stop codon, p.(Thr3085Glnfs*19). This alteration is expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay (PVS1, PM5_PTC_Strong). No effect is predicted on splicing by SpliceAI. It is not present in the population database gnomAD v2.1.1, non cancer dataset. To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. In addition, the variant was also identified in the following databases: BRCA Exchange (Pathogenic: Variant allele predicted to encode a truncated non-functional protein), ClinVar (11x pathogenic) and LOVD (3x uncertain significance, 6x pathogenoic). Based on the currently available information, c.9253del is classified as a pathogenic variant according to ClinGen-BRCA2 Guidelines version v1.0.0. -

Hereditary breast ovarian cancer syndrome

Pathogenic:3

Jan 27, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Thr3085fs variant in BRCA2 has been reported in at least 7 individuals wit h BRCA2-associated cancers (Kim 2012, Son 2012, Ou 2013, Kang 2015 ) and was abs ent from large population studies. This variant is predicted to cause a frameshi ft, which alters the protein?s amino acid sequence beginning at position 3085 an d leads to a premature termination codon 19 amino acids downstream. This alterat ion is then predicted to lead to a truncated or absent protein. Heterozygous los s of function of the BRCA2 gene is an established disease mechanism in hereditar y breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on October 18, 2016 by the ClinGen-approved ENIGMA expert panel (Clin Var SCV000324753.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. -

Apr 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Thr3085Glnfs*19) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 22382806, 23593081, 25863477). This variant is also known as 9481delA. ClinVar contains an entry for this variant (Variation ID: 52785). For these reasons, this variant has been classified as Pathogenic. -

Mar 28, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA2 c.9253delA (p.Thr3085GlnfsX19) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is also known as c.9481delA. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 248582 control chromosomes (gnomAD). c.9253delA has been reported in the literature in individuals affected with Hereditary Breast And/or Ovarian Cancer (example: Kang_2017). These data indicate that the variant is likely to be associated with disease. Nine submitters including an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.0

Mutation Taster

=0/200

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over