rs879255306

Variant names:

• chr13-32346866-CT-C
• rs879255306
• NM_000059.4:c.6980delT

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.6980delT​(p.Leu2327fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000549 in 1,458,254 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. L2327L) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 1.07
• Publications: 2 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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 13-32346866-CT-C is Pathogenic according to our data. Variant chr13-32346866-CT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 252419.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.6980delT	p.Leu2327fs	frameshift_variant	Exon 13 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.6980delT	p.Leu2327fs	frameshift_variant	Exon 13 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6611delT	p.Leu2204fs	frameshift_variant	Exon 13 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6980delT		non_coding_transcript_exon_variant	Exon 12 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000549 AC: 8 AN: 1458254 Hom.: 0 Cov.: 29 AF XY: 0.00000689 AC XY: 5 AN XY: 725464

African (AFR) AF: 0.00 AC: 0 AN: 33424

American (AMR) AF: 0.00 AC: 0 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39494

South Asian (SAS) AF: 0.00 AC: 0 AN: 85834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52702

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1110128

Other (OTH) AF: 0.00 AC: 0 AN: 60246

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

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

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

- -

Mar 25, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Likely 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Oct 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Leu2327X variant in BRCA2 has not been previously reported in individuals with hereditary breast and/or ovarian cancer (HBOC) and was absent from large population studies, but has been reported in ClinVar (Variation ID: 252419). This nonsense variant leads to a premature termination codon at position 2327, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2. -

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

- -

Feb 02, 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.Leu2327*) 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 and/or ovarian cancer (PMID: 20127978, 30322717). ClinVar contains an entry for this variant (Variation ID: 252419). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Jun 13, 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 13 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 with a personal or family history of breast and/or ovarian cancer (PMID: 20127978, 29446198, 33471991; Leiden Open Variation Database DB-ID BRCA2_005060). 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 03, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6980delT pathogenic mutation, located in coding exon 12 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 6980, causing a translational frameshift with a predicted alternate stop codon (p.L2327*). This mutation has been reported in a patient at risk for hereditary breast cancer (Morgan JE et al. Hum Mutat, 2010 Apr;31:484-91) and in a cohort of 4439 women with ovarian cancer undergoing multigene panel testing at one laboratory (Carter NJ et al. Gynecol Oncol, 2018 Dec;151:481-488). 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. -

BRCA2-related disorder Pathogenic:1

Aug 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.6980delT variant is predicted to result in premature protein termination (p.Leu2327*). This variant is also referred to as BRCA2 c.7208delT using legacy nomenclature. This variant was reported in an individual with an ovarian tumor (Supp. Table 1, Carter et al 2018. PubMed ID: 30322717) and an individual at risk of developing breast cancer (Morgan et al. 2010. PubMed ID: 20127978). This variant has not been reported in a large population database such as gnomAD, indicating this variant is rare. This variant is classified as either likely pathogenic or pathogenic by many labs in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/252419/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

May 12, 2015

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This deletion of one nucleotide is denoted BRCA2 c.6980delT at the cDNA level and p.Leu2327Ter (L2327X) at the protein level. The normal sequence, with the base that is deleted in braces, is TCTT[T]AGAG. The deletion creates a nonsense variant, which changes a Leucine to a premature stop codon. Using alternate nomenclature, this variant would be defined as BRCA2 7208delT. Although this variant has not been previously reported to our knowledge, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay, and is considered pathogenic. -

Inherited ovarian cancer (without breast cancer) Pathogenic:1

Aug 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 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1
Mutation Taster		=1/199	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: rs879255306; hg19: chr13-32921003;