rs80359679

Variant names:

• chr13-32357885-CA-C
• rs80359679
• NM_000059.4:c.7762delA

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.7762delA​(p.Ile2588TyrfsTer60) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,806 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. I2588I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:10
• Conservation: PhyloP100: 2.24
• Publications: 7 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 13-32357885-CA-C is Pathogenic according to our data. Variant chr13-32357885-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 52405.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.7762delA	p.Ile2588TyrfsTer60	frameshift_variant	Exon 16 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7762delA	p.Ile2588TyrfsTer60	frameshift_variant	Exon 16 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7393delA	p.Ile2465TyrfsTer60	frameshift_variant	Exon 16 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7762delA		non_coding_transcript_exon_variant	Exon 15 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461806 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727202

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

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

European-Non Finnish (NFE) AF: 0.00000809 AC: 9 AN: 1111976

Other (OTH) AF: 0.0000166 AC: 1 AN: 60386

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:5

Oct 01, 2016

CSER _CC_NCGL, University of Washington

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Found in a male patient having exome sequencing for an unrelated indication with a family history of breast and pancreatic cancer. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. -

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

- -

Jun 05, 2023

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.7762delA (p.Ile2588TyrfsX60) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant was absent in 251436 control chromosomes (gnomAD). c.7762delA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Lilyquist_2017). The following publication has been ascertained in the context of this evaluation (PMID: 28888541). Four submitters, including an expert panel, have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Dec 04, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Ile2588fs variant in BRCA2 has been reported in 3 individuals with breast and/or ovarian cancers (Frank 1998, Cunningham 2014; Breast Cancer Information Core database, www.research.nhgri.nih.gov/bic/). While this variant was absent from large population studies, the ability of these studies to accurately detect indels may be limited. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2588 and leads to a premature termination codon 60 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) for hereditary breast and ovarian cancer in an autosomal dominant manner based upon the predicted impact to the protein. -

Jun 11, 2014

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The interpretation for this sequence variant was made by Invitae based on the ACMG guidelines. A more detailed explanation of the interpretation for this specific variant is forthcoming. This ClinVar entry will be updated at that time. -

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

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. -

Jun 12, 2000

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 11, 2022

Genetics and Molecular Pathology, SA Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.7762del variant is classified as Pathogenic (PVS1, PS4_Moderate, PM2) This BRCA2 c.7762del variant is located in exon 16/27 and is predicted to cause a shift in the reading frame at codon 2588. BRCA2:c. 7762del (also described as BRCA1 4184del4 using legacy nomenclature) has been reported in multiple unrelated individuals and families with breast, ovarian and colon cancer (Cunningham et al., 2015 PMID: 24504028; Rosenthal et al, 2018 PMID: 30267214; Copson et al, 2018 PMID: 29337092). (Ps4_moderate) The variant has been reported in dbSNP (rs80359679) and has been reported as Pathogenic by other diagnostic laboratories (ClinVar Variation ID: 52405). It has not been reported in HGMD. literature: Frank (1998) J Clin Oncol, Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. PubMed: 9667259 -

BRCA2-related disorder Pathogenic:1

Jun 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 c.7762delA variant is predicted to result in a frameshift and premature protein termination (p.Ile2588Tyrfs*60). This variant has been reported in at least three individuals with breast/ovarian cancer (Frank et al. 1998. PubMed ID: 9667259; Cunningham et al. 2014. PubMed ID: 24504028; Copson et al. 2018. PubMed ID: 29337092). It has also been reported in an individual with multiple adenomatous polyps who was also heterozygous for a protein-truncating variant in the NTHL1 gene (Rosenthal et al. 2018. PubMed ID: 30267214). This variant has not been reported in the gnomAD database and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/52405/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Apr 18, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7762delA pathogenic mutation, located in coding exon 15 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 7762, causing a translational frameshift with a predicted alternate stop codon (p.I2588Yfs*60). This pathogenic mutation has been reported in an early-onset breast cancer family and in a series of >900 epithelial ovarian cancer patients (Frank TS et al. J. Clin. Oncol. 1998 Jul;16:2417-25; Cunningham JM et al. Sci Rep. 2014 Feb;4:4026). In one case control study, this alteration was detected in 2/2222 individuals with high-grade serous epithelial ovarian cancer and 0/1528 matched controls. (Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9). Of note, this mutation is also designated as 7990delA and I2588fs 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs80359679; hg19: chr13-32932022;