rs80359211

Variant names:

• chr13-32394812-G-A
• rs80359211
• NM_000059.4:c.9380G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-32394812-G-A
• chr13-32394812-G-C

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.9380G>A​(p.Trp3127*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,816 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 (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: 6.50
• Publications: 16 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 13-32394812-G-A is Pathogenic according to our data. Variant chr13-32394812-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38235.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	c.9380G>A	p.Trp3127*	stop_gained	Exon 25 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9380G>A	p.Trp3127*	stop_gained	Exon 25 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9011G>A	p.Trp3004*	stop_gained	Exon 25 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1438G>A		non_coding_transcript_exon_variant	Exon 24 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*1438G>A		3_prime_UTR_variant	Exon 24 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461816 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

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

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. -

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 25 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 reported in individuals affected with breast or ovarian cancer (PMID: 22752604, 25186627, 27798748, 29470806, 29785135, 33471991). 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. -

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 29, 2010

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 16, 2024

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Trp3127*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product.This premature translational stop signal has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 22752604, 25186627, 26187060, 27798748, 29470806). ClinVar contains an entry for this variant (Variation ID: 38235). This variant is also known as c.9608G>A. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:4

Mar 24, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant causes the premature termination of BRCA2 protein synthesis. It has been reported in individuals with breast and/or ovarian cancer in the published literature (PMID: 29785135 (2018), 29470806 (2018), 27798748 (2017), 22752604 (2012)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic. -

Oct 16, 2020

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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Juwle 2012, Ricci 2014, Kwong 2016, Moran 2017); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as c.9608G>A; This variant is associated with the following publications: (PMID: 26187060, 25256924, 25186627, 29470806, 17899372, 22752604, 24065114, 28152038, 27798748, 28281021, 29785135, 29446198, 32885271) -

Feb 05, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PM5_strong, PVS1 -

Jan 20, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.9380G>A; p.Trp3127Ter variant (rs80359211) has been reported in individuals with a personal history of breast cancer and in individuals with family history of hereditary breast and ovarian cancer (Rebbeck 2018, Tung 2015, Wang 2014). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 38235) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the BRCA2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated BRCA2 protein lacking the nuclear localization signal (Jeyasekharan 2013). Additionally, other truncating variants downstream are considered pathogenic (Variation IDs: 52826, 52888, 38260, 52831). Based on available information, this variant is considered pathogenic. References: Jeyasekharan AD et al. A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. Nat Struct Mol Biol. 2013 Oct;20(10):1191-8. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. Wang ET et al. BRCA1 germline mutations may be associated with reduced ovarian reserve. Fertil Steril. 2014 Dec;102(6):1723-8. -

Hereditary cancer-predisposing syndrome Pathogenic:3

May 24, 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 25 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 reported in individuals affected with breast or ovarian cancer (PMID: 22752604, 25186627, 27798748, 29470806, 29785135, 33471991). 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. -

Mar 28, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.W3127* pathogenic mutation (also known as c.9380G>A), located in coding exon 24 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9380. This changes the amino acid from a tryptophan to a stop codon within coding exon 24. This alteration has been identified in multiple individuals whose personal and/or family histories were concerning for hereditary breast and ovarian cancer syndrome (Juwle A et al. Med. Oncol. 2012 Dec;29:3272-81; Moran O et al. Breast Cancer Res. Treat. 2017 01;161:135-142; Tung N et al. Cancer. 2015 Jan;121:25-33; Singh J et al. Breast Cancer Res. Treat. 2018 Jul;170(1):189-196). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -

Jan 13, 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.9380G>A, located in exon 25 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_Str). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). The SpliceAI algorithm predicts no significant impact on splicing. To our knowledge, neither relevant clinical data nor well-stablished functional studies have been reported for this variant. It has been reported in ClinVar as a pathogenic variant. Based on currently available information, the variant c.9380G>A should be considered a pathogenic variant. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Aug 20, 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.Trp3127*) 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 and/or ovarian cancer (PMID: 22752604, 25186627, 26187060, 27798748, 29470806). This variant is also known as c.9608G>A. ClinVar contains an entry for this variant (Variation ID: 38235). For these reasons, this variant has been classified as Pathogenic. -

Apr 04, 2024

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.9380G>A (p.Trp3127X) 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. The variant was absent in 251360 control chromosomes (gnomAD). c.9380G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Juwle_2012, Tung_2014, Wang_2014, Moran_2017, Shah_2018). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22752604, 27798748, 29785135, 25186627, 25256924). ClinVar contains an entry for this variant (Variation ID: 38235). Based on the evidence outlined above, the variant was classified as pathogenic. -

Breast and/or ovarian cancer Pathogenic:1

Jul 21, 2022

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Malignant tumor of breast Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Trp3127X variant was identified in 1 of 200 proband chromosomes (frequency: 0.005) from individuals or families with early onset and sporadic breast cancer, and was not identified in 100 control chromosomes from healthy individuals (Juwle 2012).The variant was also identified in dbSNP (ID: rs80359211) as “With Pathogenic allele”; ClinVar and Clinvitae database (Pathogenic by Ambry Genetics, Sharing Clinical Reports Projects of Myriad, Breast Cancer Information Core (BIC), Quest Diagnostics, Nichols Institute, San Juan, Capistrano. Invitae did not provide a classification); Fanconi Anemia Mutation Database (LOVD) (1x classified deleterious); BIC database (5X class 5 causal with clinical importance); BRCA Share UMD (1X “causal” classification p.Trp3127X by c.9381A>G). The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict the creation of a 3’ splice site; this is not very predictive of pathogenicity. Exonic splicing enhancers (ESE) studies indicate the effect on ESE is decreased. This may adversely affect splicing and thereby contribute to BRCA2 disruption (Pettigrew 2008).The p.Trp3127X variant leads to a premature stop codon at position 3127 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -

Familial cancer of breast Pathogenic:1

Nov 14, 2022

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.61	D
BayesDel_noAF	Pathogenic	0.63
CADD	Pathogenic	46
DANN	Uncertain	0.99
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.97	D
PhyloP100		6.5
Vest4		0.94
GERP RS		5.9
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: rs80359211; hg19: chr13-32968949;