rs397507906

Variant names:

• chr13-32355087-A-AG
• rs397507906
• NM_000059.4:c.7234_7235insG

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.7234_7235insG​(p.Thr2412SerfsTer2) variant causes a frameshift change involving the alteration of a non-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: 32)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• Conservation: PhyloP100: 0.947

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 13-32355087-A-AG is Pathogenic according to our data. Variant chr13-32355087-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 52295.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.7234_7235insG	p.Thr2412SerfsTer2	frameshift_variant	Exon 14 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.7234_7235insG	p.Thr2412SerfsTer2	frameshift_variant	Exon 14 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6865_6866insG	p.Thr2289SerfsTer2	frameshift_variant	Exon 14 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.7234_7235insG		non_coding_transcript_exon_variant	Exon 13 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

May 18, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast and/or ovarian cancer (Esteban Cardenosa et al., 2010; Tazzite et al., 2012; de Juan Jimenez et al., 2013; de Juan et al., 2015; Jouali et al., 2016; Elalaoui et l., 2022); Also known as 7462_7463insG or 7462insG; This variant is associated with the following publications: (PMID: 26026974, 27129401, 24019637, 23479189, 20033483, 27446417, 24606420, 25780794, 24312913, 34242281, 28779219, 32341426, 32885271, 32778078, 35578052, 35216584, 35858847, 31060517, 22425665) -

Jan 01, 2020

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change inserts 1 nucleotide in exon 14 of the BRCA2 mRNA (c.7234_7235insG), causing a frameshift at codon 2412. This creates a premature translational stop signal 2 amino acid residues later (p.(Thr2412Serfs*2) and is expected to result in an absent or disrupted protein product. This variant has been described in the literature in an individual with breast and ovarian cancer (PMID: 20711702, 22425665, 23479189, 26026974, 27446417). Also, this variant has been defined as c.7462_7463insG, c.7234insG, c.7235insG, c.7462insG, or 7463insG in the literature. The mutation database ClinVar contains entries for this variant (Variation ID: 52295). -

Jul 23, 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. In addition, it has been reported in individuals with breast cancer in the published literature (PMID: 32885271 (2021) and 23479189 (2013)). Based on the available information, this variant is classified as pathogenic. -

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

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. -

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

- -

Malignant tumor of breast Pathogenic:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The BRCA2 p.Thr2412Serfs*2 variant was identified in 5 of 22780 proband chromosomes (frequency: 0.0002) from Moroccan and European individuals or families with breast/ovarian cancer (Tazzite 2012, Rebbeck 2018). The variant was also identified in dbSNP (ID: rs397507906) “With Pathogenic allele”, ClinVar (classified pathogenic, reviewed by an expert panel (2016); submitters: ENIGMA, CIMBA, GeneDx and GeneKor MSA), and LOVD 3.0. The variant was not identified in UMD-LSDB. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.7234_7235insG variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2412 and leads to a premature stop codon at position 2413. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Aug 08, 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.Thr2412Serfs*2) 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 a personal and family history of breast cancer (PMID: 22425665, 23479189, 28779219). This variant is also known as c.7235insG. ClinVar contains an entry for this variant (Variation ID: 52295). For these reasons, this variant 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: rs397507906; hg19: chr13-32929224;