rs80359679

Positions:

• chr13-32357885-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.7762del​(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:9
• Conservation: PhyloP100: 2.24

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 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 id is 52405.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32357885-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.7762del	p.Ile2588TyrfsTer60	frameshift_variant	16/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.7762del	p.Ile2588TyrfsTer60	frameshift_variant	16/27	5	NM_000059.4	A2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary breast ovarian cancer syndrome Pathogenic:5

Pathogenic, criteria provided, single submitter	research	CSER _CC_NCGL, University of Washington	Oct 01, 2016	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. -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 05, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 04, 2015	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. -
Pathogenic, no assertion criteria provided	clinical testing	Invitae	Jun 11, 2014	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

Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Jun 12, 2000	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Genetics and Molecular Pathology, SA Pathology	May 11, 2022	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 -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 18, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs80359679; hg19: chr13-32932022;