13-32394842-CT-CTT

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.9413dup(p.Leu3138PhefsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,810 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. T3137T) has been classified as Benign. 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:9
• Conservation: PhyloP100: -0.884

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 13-32394842-C-CT is Pathogenic according to our data. Variant chr13-32394842-C-CT is described in ClinVar as [Pathogenic]. Clinvar id is 231901.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4	c.9413dup	p.Leu3138PhefsTer12	frameshift_variant	25/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9413dup	p.Leu3138PhefsTer12	frameshift_variant	25/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727206

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

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

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, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jun 06, 2023	A known pathogenic mutation was detected in the BRCA2 gene (p.Leu3138fs). This sequence change results from a duplication of T at nucleotide position 9413 which located in coding exon 25 of the BRCA2 gene, causing a translational frameshift with a predicted alternate stop codon (p.L3138Ffs*12). This mutation has been reported in breast and breast/ovarian cancer families (PMID: 18594331, 30713775, 25007954, 26306726, 32438681). This variant known as c.9413_9414insT (c.9413dup)and c.9641insT in published literature. This variant submitted in Clinvar (ID:231901) by seven clinical laboratories all classify it as pathogenic variant . 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. Therefore, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Oct 18, 2016	Variant allele predicted to encode a truncated non-functional protein. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Mar 13, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 12, 2018	The c.9413dupT pathogenic mutation, located in coding exon 24 of the BRCA2 gene, results from a duplication of T at nucleotide position 9413, causing a translational frameshift with a predicted alternate stop codon (p.L3138Ffs*12). This mutation has been reported in breast and breast/ovarian cancer families (Marks JL et al. J. Thorac. Oncol. 2008 Jul;3(7):805; Concolino P et al. Clin. Chim. Acta 2014 Nov; 437:72-7). Of note, this alteration is also designated as c.9413_9414insT and c.9641insT 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	Sep 15, 2021	This variant inserts 1 nucleotide in exon 25 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 a hereditary breast and ovarian cancer family and in an individual affected with lung cancer with a family history of breast, lung and skin cancer (PMID: 18594331, 25007954). 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. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 07, 2022

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); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9641dup; This variant is associated with the following publications: (PMID: 18594331, 30713775, 25007954, 26306726, 32438681) -

Malignant tumor of breast Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The BRCA2 p.Leu3138PhefsX1 variant was identified by Marks et al (2008) in an individual with metastatic lung adenocarcinoma and a family history of HBOC and lung cancer. The variant was not identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), Exome Aggregation Consortium (ExAC), HGMD, LOVD, COSMIC, ClinVar, Clinvitae, ARUP Laboratories BRCA Mutations Database, GeneInsight COGR, BIC or UMD. The p.Leu3138PhefsX12 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 3138 and leads to a premature stop codon 12 codons downstream. 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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Apr 15, 2023

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 231901). This variant is also known as c.9413_9414insT (p.Leu3138_Phe3139?fs) and 9641insT. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer and lung adenocarcinoma and a family history of breast and lung cancer (PMID: 18594331, 25007954, 26306726). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu3138Phefs*12) 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). -

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: rs876659435; hg19: chr13-32968979;