13-32394842-CT-CTT

Variant names:

• chr13-32394842-C-CT
• rs876659435
• NM_000059.4:c.9413dupT

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.9413dupT​(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 (★★★). 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:10
• 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 rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.9413dupT	p.Leu3138PhefsTer12	frameshift_variant	Exon 25 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.9413dupT	p.Leu3138PhefsTer12	frameshift_variant	Exon 25 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.9044dupT	p.Leu3015PhefsTer12	frameshift_variant	Exon 25 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*1471dupT		non_coding_transcript_exon_variant	Exon 24 of 26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*1471dupT		3_prime_UTR_variant	Exon 24 of 25	2		ENSP00000506251.1

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:10

Revision: reviewed by expert panel

Submissions by phenotype

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

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

- -

Jun 06, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 18, 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. -

Hereditary cancer-predisposing syndrome Pathogenic:3

Sep 15, 2021

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 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. -

Sep 12, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 13, 2022

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Sep 22, 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.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). This variant is not present in population databases (gnomAD no frequency). 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 also known as c.9413_9414insT (p.Leu3138_Phe3139?fs) and 9641insT. ClinVar contains an entry for this variant (Variation ID: 231901). For these reasons, this variant has been classified as Pathogenic. -

Sep 12, 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.9413dupT (p.Leu3138PhefsX12; also described as c.9413_9414insT in the literature) 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 251358 control chromosomes (gnomAD). c.9413dupT has been reported in the literature in several individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (example: Rebbeck_2018). The following publication has been ascertained in the context of this evaluation (PMID: 29446198). ClinVar contains an entry for this variant (Variation ID: 231901). Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Jun 07, 2022

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); 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

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

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;