chr13-32379893-A-AT

Variant names:

• chr13-32379893-A-AT
• rs1555288494
• NM_000059.4:c.9097_9098insT

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.9097_9098insT​(p.Thr3033IlefsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.31

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 13-32379893-A-AT is Pathogenic according to our data. Variant chr13-32379893-A-AT is described in ClinVar as [Pathogenic]. Clinvar id is 409583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9097_9098insT	p.Thr3033IlefsTer11	frameshift_variant	Exon 23 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9097_9098insT	p.Thr3033IlefsTer11	frameshift_variant	Exon 23 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.8728_8729insT	p.Thr2910IlefsTer11	frameshift_variant	Exon 23 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1155_*1156insT		non_coding_transcript_exon_variant	Exon 22 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*1155_*1156insT		3_prime_UTR_variant	Exon 22 of 25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.000224 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

May 17, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant causes the premature termination of BRCA2 protein synthesis. It has been described in individuals with pancreatic cancer, breast cancer, and breast and/or ovarian cancer in the published literature (PMID: 25940717 (2015), 25556971 (2015), 22970155 (2012), 9150172 (1997)). In addition, this variant has been reported in a four year old female child with Fanconi Anemia (PMID 21138478 (2011)). The frequency of this variant in the general population is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Jul 04, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Oct 03, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9097_9098insT pathogenic mutation, located in coding exon 22 of the BRCA2 gene, results from an insertion of one nucleotide at position 9097, causing a translational frameshift with a predicted alternate stop codon (p.T3033Ifs*11). This alteration has been reported in an individual with clinical suspicion of hereditary breast/ovarian cancer syndrome (Trujillano D et al. J Mol Diagn. 2015 Mar;17:162-70). 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. -

Jan 15, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant inserts 1 nucleotide in exon 23 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 identified in 1/31398 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Oct 14, 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.9097_9098insT (p.Thr3033IlefsX11) 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 was absent in 249460 control chromosomes. c.9097_9098insT has been reported in the literature in at-least one individual affected with Hereditary Breast And Ovarian Cancer (example: Trujillano_2015). The following publication has been ascertained in the context of this evaluation (PMID: 25556971). ClinVar contains an entry for this variant (Variation ID: 409583). Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 29, 2024

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.Thr3033Ilefs*11) 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 (no rsID available, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with hereditary breast and/or ovarian cancer syndrome (PMID: 25556971). ClinVar contains an entry for this variant (Variation ID: 409583). For these reasons, this variant has been classified as Pathogenic. -

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

-

Institute of Genomics, University of Tartu

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

BRCA2-related cancer predisposition Pathogenic:1

Sep 27, 2024

All of Us Research Program, National Institutes of Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9097_9098insT variant in the BRCA2 gene is located on the exon 23 and is predicted to cause shift of reading frame which introduces a premature translation termination codon (p.Thr3033Ilefs*11), resulting in an absent or disrupted protein product. The variant has been reported from an individual with hereditary breast and ovarian cancer (PMID: 25556971). Other protein truncating variants located in the same exon (p.Tyr3006*, p.Gln3037*) have been interpreted as pathogenic by the expert panel (ClinVar ID: 52728, 52752). Loss-of-function variants in the BRCA2 gene are known to cause hereditary breast and ovarian cancer (PMID: 8988179, 11897832, 29446198). This variant has been classified as pathogenic by multiple submitters in ClinVar (ID: 409583). This variant is rare in the general population according to gnomAD (1/31398 chromosomes). Therefore, the c.9097_9098insT (p.Thr3033Ilefs*11) variant in the BRCA2 gene has been classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

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: rs1555288494; hg19: chr13-32954030;