13-32338598-G-T

Variant names:

• chr13-32338598-G-T
• rs397507327
• NM_000059.4:c.4243G>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.4243G>T​(p.Glu1415*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000693 in 1,443,902 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 Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. E1415E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:15
• Conservation: PhyloP100: 1.15
• Publications: 8 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: 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 13-32338598-G-T is Pathogenic according to our data. Variant chr13-32338598-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 37890.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.4243G>T	p.Glu1415*	stop_gained	Exon 11 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.4243G>T	p.Glu1415*	stop_gained	Exon 11 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.4243G>T	p.Glu1415*	stop_gained	Exon 11 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.4243G>T	p.Glu1415*	stop_gained	Exon 11 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.4243G>T	p.Glu1415*	stop_gained	Exon 11 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.3874G>T	p.Glu1292*	stop_gained	Exon 11 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.93e-7 AC: 1 AN: 1443902 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 715146

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

African (AFR) AF: 0.00 AC: 0 AN: 32736

American (AMR) AF: 0.00 AC: 0 AN: 42936

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25746

East Asian (EAS) AF: 0.00 AC: 0 AN: 39332

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53218

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101732

Other (OTH) AF: 0.00 AC: 0 AN: 59560

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

Alfa AF: 0.000103 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:15

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6

Apr 30, 2018

Counsyl

Significance: Pathogenic

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.

Sep 08, 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

Dec 30, 2017

Department of Genetics, Sultan Qaboos University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Aug 19, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 19, 2023

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in 5 individuals affected with breast, ovarian and fallopian tube cancer (PMID: 22006311, 30322717, 33471991; Leiden Open Variation Database DB-ID BRCA2_002639; Color internal data). 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.

Hereditary cancer-predisposing syndrome Pathogenic:3

Jan 27, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in multiple individuals affected with breast, ovarian and fallopian tube cancer (PMID: 22006311, 30322717, 33471991; Leiden Open Variation Database DB-ID BRCA2_002639; Color internal data). 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.

Sep 28, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E1415* pathogenic mutation (also known as c.4243G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 4243. This changes the amino acid from a glutamic acid to a stop codon within coding exon 10. This alteration has been previously reported in individuals diagnosed with ovarian cancer (Walsh T et al. Proc. Natl. Acad. Sci. U.S.A. 2011 Nov;108:18032-7; Carter NJ et al. Gynecol. Oncol., 2018 12;151:481-488) and in an individual diagnosed with a head and neck squamous cell cancer (Chandrasekharappa SC et al. Cancer, 2017 Oct;123:3943-3954). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). Of note, this alteration is also designated as "4471G>T" 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.

Jun 25, 2025

Molecular Diagnostics Laboratory, Catalan Institute of Oncology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1, PM2_Supporting, PM5_PTC_Strong c.4243G>T, located in exon 11 of the BRCA2 gene, is a nonsense variant expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay (PVS1, PM5_PTC_Strong). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_Supporting). No effect is predicted on splicing by SpliceAI. To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. It has been reported as a pathogenic variant in ClinVar, BRCA Exchange and LOVD databases. Based on the currently available information, c.4243G>T is classified as a pathogenic variant according to ClinGen-BRCA2 Guidelines version 1.0.

not provided Pathogenic:2

Aug 07, 2019

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 29, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Walsh et al., 2011; Kluska et al., 2015); Also known as 4471G>T; This variant is associated with the following publications: (PMID: 34413315, 22006311, 25948282, 28678401, 29446198, 30322717, AlHinai2021[CaseReport], 31853058, 32377563)

Hereditary breast ovarian cancer syndrome Pathogenic:2

Jul 05, 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.4243G>T (p.Glu1415X) 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 4471G>T.Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 242558 control chromosomes (gnomAD). c.4243G>T has been reported in the literature in individuals affected with hereditary breast cancer, ovarian cancer, fallopian tube carcinoma, head and neck squamous cell carcinoma (examples: Walsh_2011, Chandrasekharappa_2017, Carter_2018, and Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Ten 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.

Nov 04, 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.Glu1415*) 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 fallopian tube carcinoma or head and neck squamous cell carcinoma (PMID: 22006311, 28678401). This variant is also known as c.4471G>T (p.Glu1416X). ClinVar contains an entry for this variant (Variation ID: 37890). For these reasons, this variant has been classified as Pathogenic.

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 Pathogenic:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial cancer of breast Pathogenic:1

Jan 30, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Uncertain	0.31
Eigen_PC	Benign	0.0034
FATHMM_MKL	Benign	0.41	N
PhyloP100		1.2
Vest4		0.91
GERP RS		4.2
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs397507327; hg19: chr13-32912735;