13-32398437-C-G

Variant names:

• chr13-32398437-C-G
• rs4987049
• NM_000059.4:c.9924C>G

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.9924C>G​(p.Tyr3308*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,614,022 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. Y3308Y) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:17
• Conservation: PhyloP100: -1.53
• Publications: 26 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 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32398437-C-G is Pathogenic according to our data. Variant chr13-32398437-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 52916.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.9924C>G	p.Tyr3308*	stop_gained	Exon 27 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9924C>G	p.Tyr3308*	stop_gained	Exon 27 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9555C>G	p.Tyr3185*	stop_gained	Exon 27 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1982C>G		non_coding_transcript_exon_variant	Exon 26 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*1982C>G		3_prime_UTR_variant	Exon 26 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251252 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727230

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152154 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41424

American (AMR) AF: 0.0000655 AC: 1 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2092

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5

Feb 06, 2018

Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

A heterozygous c.9924C>G (p.Y3308*) pathogenic variant in the BRCA2 gene was detected in this individual. This variant has been previously described in multiple individuals with breast, colorectal, and ovarian cancer (PMID: 17026620, 22711857). In addition, functional studies have shown that the c.9924C>G (p.Y3308*) variant alters homologous recombination and increases chromosomal aberrations in cells (PMID: 18593900, 18607349). Therefore, we consider this variant to be pathogenic.

Feb 08, 2013

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 20, 2004

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 22, 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

Hereditary breast ovarian cancer syndrome Pathogenic:4

Mar 18, 2021

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr3308X variant in BRCA2 has been reported in at least 16 individuals with hereditary breast/ovarian cancer (HBOC) (Naseem 2006 PMID: 17026620, Alsop 2012 PMID: 22711857, Rebbeck 2018 PMID: 29446198, LMM data). It has also been identified in 0.002% (2/113582) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant was classified as pathogenic on 06/09/16 by the ClinGen-approved ENIGMA expert panel (ClinVar Variation ID 52916). This nonsense variant leads to a premature termination codon at position 3308. This alteration occurs within the last exon and is, therefore, likely to escape nonsense mediated decay (NMD) and result in a truncated protein. In vitro and in vivo functional studies support that this variant impacts protein function (Hucl 2008 PMID: 18593900, Kuznetsov 2008 PMID: 18607349). Furthermore, another variant resulting in the same premature termination codon (c.9924C>A, p.Tyr3308X) has been identified in individuals with HBOC (Rebbeck 2018 PMID: 29446198). Although the presence of a benign loss-of-function (LOF) variant 18 amino acids downstream of this nonsense variant suggests there is some tolerance to LOF variants at the 3' end of this exon, the available evidence supports that protein truncation at the p.3308 position is disease-causing. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast/ovarian cancer. ACMG/AMP Criteria applied: PS4, PVS1_Strong, PM2_Supporting, PS3_Supporting.

Nov 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.Tyr3308*) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 111 amino acid(s) of the BRCA2 protein. This variant is present in population databases (rs4987049, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast cancer, colorectal cancer, and/or ovarian cancer (PMID: 17026620, 22711857). This variant is also known as 10152C>G. ClinVar contains an entry for this variant (Variation ID: 52916). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects BRCA2 function (PMID: 18593900, 18607349). For these reasons, this variant has been classified as Pathogenic.

Aug 27, 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.9924C>G (p.Tyr3308X) 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 allele was found at a frequency of 8e-06 in 251252 control chromosomes. c.9924C>G has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Alsop_2012, Krainer_1999, Offit_2002). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in defective homologous recombination (e.g. Kuznetsov_2008). The following publications have been ascertained in the context of this evaluation (PMID: 14559878, 22711857, 18607349, 24323938, 22678057, 18593900, 9145678). ClinVar contains an entry for this variant (Variation ID: 52916). Based on the evidence outlined above, the variant was classified as pathogenic.

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

not provided Pathogenic:2

Jan 11, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This nonsense variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000018 (2/113582 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer, ovarian cancer, and bladder cancer (PMIDs: 32427313 (2020), 31360904 (2019), 22711857 (2012), 17026620 (2006), 8896551 (1996)). In addition, this variant has been reported to have a damaging effect on BRCA2 protein function (PMIDs: 22678057 (2012), 18593900 (2008), 18607349 (2008)). Based on the available information, this variant is classified as pathogenic.

Dec 25, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Published functional studies demonstrate a damaging effect: sensitivity to DNA damaging agents, reduced homologous repair activity, genomic instability, and decreased RAD51 focus formation (Hucl 2008, Kuznetsov 2008); Observed in several individuals with personal and/or family histories of breast or ovarian cancer (Krainer 1997, Naseem 2006, Waddell 2008, Alsop 2012); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 10152C>G; This variant is associated with the following publications: (PMID: 18607349, 26317927, 27443740, 9145678, 18097605, 20104584, 17026620, 22678057, 14559878, 25639900, 22711857, 18593900, 24323938, 27498558, 18497862, 8896551, 29446198, 30720243, 31447099, 32427313, 30787465, 31360904, 32322110)

Hereditary cancer-predisposing syndrome Pathogenic:2

Jan 27, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y3308* pathogenic mutation (also known as c.9924C>G), located in coding exon 26 of the BRCA2 gene, results from a C to G substitution at nucleotide position 9924. This changes the amino acid from a tyrosine to a stop codon within coding exon 26. This alteration occurs at the 3' terminus of theBRCA2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 111 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Naseem H et al. Clin. Genet. 2006 Nov;70:388-95; Alsop K et al. J Clin Oncol, 2012 Jul;30:2654-63; Palmer JR et al. J Natl Cancer Inst, 2020 12;112:1213-1221). Functional studies have demonstrated that this mutation has reduced cell viability, sensitivity to DNA damaging drugs, and diminished RAD51 focus formation (Kuznetsov SG et al. Nat. Med. 2008 Aug;14:875-81; Hucl T et al. Cancer Res. 2008 Jul;68:5023-30). This alteration is also known as 10152C>G in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Dec 13, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant creates a nonsense mutation in exon 27 of the BRCA2 gene, creating a premature translation stop signal that is predicted to truncate the TR2/RAD51 binding domain and a nuclear localization signal. This variant is expected to result in a non-functional protein product. Functional studies reported this variant to be abnormal in RAD51 foci formation, sensitivity to DNA damaging agents, and chromosomal aberration assays in complementation of human and mouse BRCA2-deficient cells (PMID: 18593900, 18607349). This variant has also been reported in individuals affected with breast cancer (PMID: 9145678, 17026620, 18497862; Color internal data) and ovarian cancer (PMID: 22711857; Color internal data). This variant has been identified in 2/251252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.

Breast and/or ovarian cancer Pathogenic:1

Jul 06, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inherited breast cancer and ovarian cancer Pathogenic:1

Oct 15, 2024

Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1,PM5_Strong

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.Tyr3308X variant was identified in 3 of 2250 proband chromosomes (frequency: 0.00133) from individuals and families with breast, ovarian, and colorectal cancer (Naseem 2006 PMID 17026620, Alsop 2012 PMID 22711857, Krainer 1997 PMID 9145678). The variant was also identified in dbSNP (ID: rs4987049) as “With Pathogenic, other allele”, in ClinVar (classified as pathogenic 11x by Ambry, Breast Cancer Information Core, CHEO, Color Genomics, CIMBA, ENIGMA, GeneDx, Invitae, Laboratory Corporation of America, Research Molecular Genetics Laboratory at Women's College Hospital, and SCRP), in Clinvitae (classified as pathogenic), in COGR (classified as pathogenic by CHEO, and likely pathogenic/pathogenic by COGR consensus), in LOVD 3.0, and in ARUP Laboratories (classified as definitely pathogenic). The variant was not identified in Cosmic, MutDB, or Zhejiang University Database. The variant was identified in control databases in 2 of 246006 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 2 of 111506 chromosomes (freq: 0.000018), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. Functional studies on p.Tyr3308X demonstrate that this variant has a deleterious effect (see examples Kuznetsov 2009 PMID 18607349, Hucl 2008 PMID 18593900). Kuznetsov demonstrates that this variant causes reduced cell viability, sensitivity to DNA damaging drugs, defective nonhomologous end joining (Kuznetsov 2009 PMID 18607349). The c.9924C>G variant leads to a premature stop codon at position 3308 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

Aug 18, 2023

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	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	33
DANN	Benign	0.93
DEOGEN2	Benign	0.0	.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.0	.;.
MetaRNN	Benign	0.0	.;.
MutationAssessor	Benign	0.0	.;.
PhyloP100		-1.5
PROVEAN	Benign	0.0	.;.
REVEL	Benign	0.0
Sift	Pathogenic	0.0	.;.
Sift4G	Pathogenic	0.0	.;.
Vest4		0.64
GERP RS		-1.6
Mutation Taster		=3/197	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: rs4987049; hg19: chr13-32972574; COSMIC: COSV99061404; COSMIC: COSV99061404;