13-32337464-C-T

Variant names:

• chr13-32337464-C-T
• rs80358557
• NM_000059.4:c.3109C>T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.3109C>T​(p.Gln1037*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,092 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. Q1037Q) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: BRCA2 NM_000059.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:16 O:1
• Conservation: PhyloP100: 0.911

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 13-32337464-C-T is Pathogenic according to our data. Variant chr13-32337464-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37819.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337464-C-T is described in Lovd as [Pathogenic]. Variant chr13-32337464-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.3109C>T	p.Gln1037*	stop_gained	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.3109C>T	p.Gln1037*	stop_gained	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.2740C>T	p.Gln914*	stop_gained	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.3109C>T		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249392 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134770

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460092 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 726248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:16 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3 Other:1

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. -

Nov 07, 2011

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

- -

-

Breast Cancer Information Core (BIC) (BRCA2)

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Feb 03, 2025

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.Gln1037*) 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 present in population databases (rs80358557, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 10874312, 18489799, 19353265, 20104584, 22970155, 26187060, 26757417, 26852015). It is commonly reported in individuals of Asian ancestry (PMID: 10874312, 18489799, 19353265, 20104584, 22970155, 26187060, 26757417, 26852015). This variant is also known as 3337C>T. ClinVar contains an entry for this variant (Variation ID: 37819). For these reasons, this variant has been classified as Pathogenic. -

Jan 22, 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.3109C>T (p.Gln1037X) 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 4e-06 in 251478 control chromosomes. c.3109C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Kwong_2012, Ng_2016, Lang_2017). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 22970155, 26757417, 28294317). ClinVar contains an entry for this variant (Variation ID: 37819). 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 02, 2023

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; Reported as a Chinese founder variant, observed in individuals with breast and/or ovarian cancer (Khoo et al., 2000; Liede et al., 2002; Machackova et al., 2008; Kwong et al., 2009; Cao et al., 2016; Yang et al., 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 3337C>T; This variant is associated with the following publications: (PMID: 10874312, 24824628, 25525159, 24312913, 29752822, 28724667, 30078507, 29446198, 30720243, 30702160, 31174498, 30093976, 30972954, 22970155, 11857749, 19353265, 20396944, 26852015, 21901790, 27157322, 20104584, 18489799, 12181777, 19241424, 23318652, 18779604, 26757417, 20950396, 28176296, 28918466, 28664506, 28961279, 29681614, 29805665, 28664449, 29566657, 29128982, 29202330, 29625052, 29487695, 28692638, 28294317, 26556299, 28993434, 32318955, 32885271, 31957001, 31742824, 33054725, 32029870, 32091409, 32719484, 31825140, 30875412, 30982232, 32101877, 30787465, 33646313, 29922827) -

May 17, 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. In addition, it has been described a recurrent founder mutation in individuals with breast cancer of Chinese ethnicity (PMID: 32318955 (2020), 31957001 (2020), 30982232 (2019), 29566657 (2018), 28993434 (2018), 28692638 (2017), 28664506 (2017), 28294317 (2017), 26852015 (2016), 26757417 (2016)). The frequency of this variant in the general population is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jul 22, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q1037* pathogenic mutation (also known as c.3109C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 3109. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This alteration was reported in a Chinese female who was diagnosed with mucinous ovarian adenocarcinoma at age 64, with no family history of cancer (Khoo US et al. Hum Mutat, 2000 Jul;16:88-9). Numerous Chinese families with breast and/or ovarian cancer have been reported with this alteration, and haplotype analyses have proven this to be a Chinese founder mutation (Kwong A et al. Breast Cancer Res Treat, 2009 Oct;117:683-6; Kwong A et al. PLoS One, 2012 Sep;7:e43994; Lang GT et al. Int J Cancer, 2017 Jul;141:129-142). This mutation has also been detected twice in Pakistani individuals diagnosed with early onset breast cancer (Liede A et al. Am J Hum Genet, 2002 Sep;71:595-606). Of note, this alteration is also designated as 3337C>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. -

Jul 19, 2021

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. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in over 25 individuals and families affected with breast and/or ovarian cancer (PMID: 10874312, 11857749, 12181777, 18489799, 22970155, 26187060, 28294317, 28664506, 29752822, 33471991; Leiden Open Variation Database DB-ID BRCA2_004452). This variant is a common pathogenic variant in individuals of Chinese ancestry (PMID: 26187060). This variant has been identified in 1/249392 chromosomes 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. -

Familial cancer of breast Pathogenic:2

-

Center for Precision Medicine, Meizhou People's Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 07, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;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

- -

Breast and/or ovarian cancer Pathogenic:1

Nov 25, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

BRCA2-related disorder Pathogenic:1

Feb 23, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.3109C>T variant is predicted to result in premature protein termination (p.Gln1037*). This variant has been reported in multiple individuals with breast and/or ovarian cancer (see for example, Table S2, Kwong et al. 2015. PubMed ID: 26187060; Table 1, Cao et al. 2016. PubMed ID: 26852015; Table 6, Akbar et al. 2022. PubMed ID: 35710434). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. This variant has been classified as pathogenic by an expert panel in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37819/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Malignant tumor of breast Pathogenic:1

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Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Gln1037X variant was identified in 20 of 4154 proband chromosomes (frequency: 0.005) from Chinese, Malaysian and Pakistani individuals or families with HBOC, ovarian or breast cancer and was not identified in 200 control chromosomes from healthy individuals (Liede 2002, Khoo 2000, Kurian 2008, Ng 2016, Yang 2017, Kwong 2012, Cao 2016). Haplotype analysis was performed on family members and unrelated BRCA negative Chinese control individuals and with the exception of the controls all carriers shared the same haplotype, suggesting the variant is a founder mutation in the Chinese population (Kwong 2012). The variant was also identified in dbSNP (ID: rs80358557) as “With Pathogenic, Uncertain significance allele”, in ClinVar (classified as pathogenic, reviewed by an expert panel 2016; submitters: ENIGMA, CIMBA, Invitae, GeneDx, Ambry Genetics, SCRP, and BIC), Clinvitae (4x), COGR (classified as pathogenic by 2 clinical laboratories), LOVD 3.0 (1x), BIC Database (5x, classified as pathogenic), ARUP Laboratories (classified as definitely pathogenic), Zhejiang University Database (3x), and was not identified in Cosmic, MutDB, and UMD-LSDB. The variant was identified in control databases in 1 of 244370 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017), in the East Asian population in 1 of 17218 chromosomes (freq: 0.00006); it was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, Finnish, and South Asian populations. The c.3109C>T variant leads to a premature stop codon at position 1037 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.81	D
Vest4		0.83
GERP RS		4.0

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

LitVar

Other links and lift over

dbSNP: rs80358557; hg19: chr13-32911601;