rs80359720

Positions:

• chr13-32371052-C-CT

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.8585dupT​(p.Glu2863fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). 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 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 7.64

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 (HGNC:):

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 13-32371052-C-CT is Pathogenic according to our data. Variant chr13-32371052-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 38170.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8585dupT	p.Glu2863fs	frameshift_variant	20/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8585dupT	p.Glu2863fs	frameshift_variant	20/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8216dupT	p.Glu2740fs	frameshift_variant	20/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*643dupT		non_coding_transcript_exon_variant	19/26	2		ENSP00000506251.1
BRCA2	ENST00000614259.2	n.*643dupT		3_prime_UTR_variant	19/26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	Feb 20, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	May 03, 2020	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Apr 22, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 28, 2023	This variant inserts 1 nucleotide in exon 20 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least three individuals affected with breast and/or ovarian cancer (PMID: 25186627, 26976419, 31451522, 36605468) and in more than 10 suspected hereditary breast and ovarian cancer families (PMID: 12601471, 29446198, 33754277). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 23, 2016	Variant summary: The BRCA2 c.8585dupT (p.Glu2863Argfs) frameshift variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Mutation taster predicts a damaging outcome for this variant. This variant is absent in 121206 control chromosomes while it was reported in HBOC patients indicating pathogenicity. The variant is located in a close proximity to other known pathogenic variants, such as c.8575delC (p.Gln2859Lysfs), c.8594dupT (p.Leu2865Phefs). These variants have been reported in UMD, BIC and HGMD > 25 times with a classification of pathogenic, indicating that the variant in interest is located in a mutational hot spot and further supporting a deleterious impact. The variant in interest shows strong evidence for pathogenicity: it is a truncating variant, located in a mutational hot spot, it is absent from controls (ExAC). Furthermore, reputable databases and clinical diagnostic centers classify this variant as pathogenic. Taken together the variant was classified as a Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 12, 2023	This sequence change creates a premature translational stop signal (p.Glu2863Argfs*6) 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 cancer (PMID: 12601471, 26976419). This variant is also known as 8813_8814insT. ClinVar contains an entry for this variant (Variation ID: 38170). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 10, 2023	Frameshift 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in individuals with BRCA2-related cancers (Scott et al., 2003; Tung et al., 2016; Lilyquist et al., 2017; Taylor et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8813dup, 8813insT, 8813_8814insT, 8585_8586insT; This variant is associated with the following publications: (PMID: 26976419, 21702907, 12601471, 28067867, 28281021, 30787465, 33754277, 33804961, 31723001, 29446198, 32338768, 35912641, 14732925, 20104584, 25186627, 31451522, 28888541, 32918181) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 18, 2021	This frameshift variant causes the premature termination of BRCA2 protein synthesis. It has been reported in individuals and families with breast cancer in the published literature (PMID: 26976419 (2016), 25186627 (2015), 12601471 (2003)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 14, 2024	The c.8585dupT pathogenic mutation, located in coding exon 19 of the BRCA2 gene, results from a duplication of T at nucleotide position 8585, causing a translational frameshift with a predicted alternate stop codon (p.E2863Rfs*6). This mutation has been reported in multiple breast cancer cohorts (Scott CL et al. Hum. Genet., 2003 May;112:542-51; Tung N et al. J Clin Oncol, 2016 May;34:1460-8; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Ebrahimi E et al. Cancer Prev Res (Phila), 2019 Nov;12:763-770). Of note, this alteration is also designated as 8813_8814insT and 8585_8586insT 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 15, 2023	This variant inserts 1 nucleotide in exon 20 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least three individuals affected with breast and/or ovarian cancer (PMID: 25186627, 26976419, 31451522, 36605468) and in more than 10 suspected hereditary breast and ovarian cancer families (PMID: 12601471, 29446198, 33754277). 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. -

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: rs80359720; hg19: chr13-32945189;