rs398122618

Variant names:

• chr13-32398192-CA-C
• rs398122618
• NM_000059.4:c.9682delA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.9682delA​(p.Ser3228ValfsTer21) 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. S3228S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:11
• Conservation: PhyloP100: -0.971
• Publications: 10 publications found

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]

BRCA2 Gene-Disease associations (from GenCC):

• breast-ovarian cancer, familial, susceptibility to, 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• Fanconi anemia complementation group D1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
• pancreatic cancer, susceptibility to, 2

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• sarcoma

  Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
• hereditary breast ovarian cancer syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• medulloblastoma

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 63 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32398192-CA-C is Pathogenic according to our data. Variant chr13-32398192-CA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 91530.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	NM_000059.4	MANE Select	c.9682delA	p.Ser3228ValfsTer21	frameshift	Exon 27 of 27	NP_000050.3
	BRCA2	NM_001432077.1		c.9682delA	p.Ser3228ValfsTer21	frameshift	Exon 27 of 27	NP_001419006.1
	BRCA2	NM_001406720.1		c.9631delA	p.Ser3211ValfsTer21	frameshift	Exon 27 of 27	NP_001393649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	BRCA2	ENST00000380152.8	TSL:5 MANE Select	c.9682delA	p.Ser3228ValfsTer21	frameshift	Exon 27 of 27	ENSP00000369497.3
	BRCA2	ENST00000544455.6	TSL:1	c.9682delA	p.Ser3228ValfsTer21	frameshift	Exon 27 of 27	ENSP00000439902.1
	BRCA2	ENST00000530893.7	TSL:1	c.9313delA	p.Ser3105ValfsTer21	frameshift	Exon 27 of 27	ENSP00000499438.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249942 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4

Oct 18, 2012

Sharing Clinical Reports Project (SCRP)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Mar 02, 2020

BRCAlab, Lund University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Pathogenic:2

Nov 03, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in the published literature (Dodova et al., 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9910delA; This variant is associated with the following publications: (PMID: 29310832, 26183948, 30720243, 31159747, 29922827)

Feb 23, 2018

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

Feb 16, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 1 nucleotide in exon 27 of the BRCA2 gene, creating a frameshift and premature translation stop signal in the last coding exon. This variant is predicted to escape nonsense-mediated decay and be expressed as a truncated protein. Although functional studies have not been reported, this variant is expected to disrupt the RAD51 binding domain. This domain has been reported to be essential for homologous recombination and DNA repair (PMID: 17515903), therefore this variant is expected to result in an absent or non-functional protein product. In addition, truncating variants occurring downstream of this variant are classified as pathogenic (ClinVar Variation ID: 1069551, 823404, 548323). This variant has been reported in individuals affected with high-risk breast cancer (PMID: 26183948, 35261632; Color internal data). This variant has been identified in 1/249942 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.

Oct 18, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9682delA pathogenic mutation, located in coding exon 26 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 9682, causing a translational frameshift with a predicted alternate stop codon (p.S3228Vfs*21). This alteration occurs at the 3' terminus of theBRCA2 gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 6% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This mutation was observed in a Bulgarian woman with bilateral breast cancer diagnosed at age 52 (Dodova RI et al. BMC Cancer 2015 Jul;15:523). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Hereditary breast ovarian cancer syndrome Pathogenic:2

Jun 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26183948). This sequence change creates a premature translational stop signal (p.Ser3228Valfs*21) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 191 amino acid(s) of the BRCA2 protein. This variant is present in population databases (rs398122618, gnomAD 0.0009%). ClinVar contains an entry for this variant (Variation ID: 91530). This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Tyr3308*) have been determined to be pathogenic (PMID: 17026620, 18593900, 18607349, 22711857). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

May 15, 2025

GeneKor MSA

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The genetic variant is a deletion of a single nucleotide in exon 27 of the BRCA2 gene (c.9682delA). This deletion causes a frameshift and leads to the creation of a premature stop codon 21 amino acids downstream – p.(Ser3228Valfs*21). As a result, protein synthesis is prematurely terminated, leading to the loss of function of one allele of the gene.This variant is listed in the ClinVar database (VCV000091530.22) and is classified as pathogenic.

Breast carcinoma Pathogenic:1

Aug 08, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.97
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs398122618; hg19: chr13-32972329;