rs397507849

Variant names:

• chr13-32340746-AAATT-A
• rs397507849
• NM_000059.4:c.6393_6396delATTA

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.6393_6396delATTA​(p.Lys2131AsnfsTer5) 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: 33)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: 1.60

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 13-32340746-AAATT-A is Pathogenic according to our data. Variant chr13-32340746-AAATT-A is described in ClinVar as [Pathogenic]. Clinvar id is 52080.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340746-AAATT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.6393_6396delATTA	p.Lys2131AsnfsTer5	frameshift_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.6393_6396delATTA	p.Lys2131AsnfsTer5	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.6024_6027delATTA	p.Lys2008AsnfsTer5	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.6393_6396delATTA		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

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

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. -

Apr 21, 2016

Michigan Medical Genetics Laboratories, University of Michigan

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:3

Dec 05, 2018

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 29, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This deletion of four nucleotides in BRCA2 is denoted c.6393_6396delATTA at the cDNA level and p.Lys2131AsnfsX5 (K2131NfsX5) at the protein level. Using alternate nomenclature, this variant has been published as BRCA2 6621del4. The normal sequence, with the bases that are deleted in brackets, is TTAA[delATTA]TCAA. The deletion causes a frameshift which changes a Lysine to an Asparagine at codon 2131, and creates a premature stop codon at position 5 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.6393_6396delATTA has been observed in at least two individuals with ovarian cancer as well as in a male with breast cancer whose tumor showed loss of the wild-type BRCA2 allele (Kwiatkowska 2002, Brozek 2008, Koczkowska 2016). We consider this variant to be pathogenic. -

Nov 30, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in patients affected with breast and/or ovarian cancer (PMIDs: 27167707 (2016), 17997147 (2008), 12114492 (2002)). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Dec 11, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 4 nucleotides in exon 11 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 two individuals affected with ovarian cancer, a male individual affected with breast cancer, and in an individual with a personal or family history of breast cancer (PMID: 12114492, 17997147, 27167707, 35464868). 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. -

Apr 13, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.6393_6396delATTA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 6393 to 6396, causing a translational frameshift with a predicted alternate stop codon (p.K2131Nfs*5). This mutation has been reported in a Polish family with two cases of male breast cancer (Kwiatkowska E et al. J. Med. Genet. 2002 Jul;39:E35), and in Polish ovarian cancer patients (Brozek I et al. Gynecol. Oncol. 2008 Feb;108:433-7; Koczkowska M et al. Cancer Med. 2016 Jul;5:1640-6). 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:2

Oct 04, 2023

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.6393_6396delATTA (p.Lys2131AsnfsX5) 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 241088 control chromosomes. c.6393_6396delATTA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g., Kwiatkowska_2002; Van der Merwe_2022). The following publications have been ascertained in the context of this evaluation (PMID: 12114492, 35464868). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, and all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 17, 2023

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.Lys2131Asnfs*5) 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/or ovarian cancer (PMID: 12114492, 17997147, 27167707). This variant is also known as 6621del4. ClinVar contains an entry for this variant (Variation ID: 52080). For these reasons, this variant has been classified as Pathogenic. -

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.6393_6396del variant in the BRCA2 gene is located on the exon 11 is predicted to cause shift of reading frame which introduces a premature translation termination codon (p.Lys2131Asnfs*5), resulting in an absent or disrupted protein product. The variant has been reported in individuals with breast and/or ovarian Cancer (PMID: 17997147, 35464868, 31575519, 31853058). The other protein termination codon variants located in the same exon (p.Ser1404*, p.Gln2160*, p.Cys2256*) have been interpreted as pathogenic (ClinVar ID: 91815, 266950, 52180). 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 reported in ClinVar as pathogenic by the expert panel (ID: 52080). The variant is absent in the general population database (gnomAD). Therefore, the c.6393_6396del (p.Lys2131Asnfs*5) 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: rs397507849; hg19: chr13-32914883;