NM_000059.4:c.3717delA

Variant names:

• chr13-32338069-GA-G
• rs80359401
• NM_000059.4:c.3717delA

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.3717delA​(p.Lys1239AsnfsTer20) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,360 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. K1239K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:14
• Conservation: PhyloP100: 2.11
• Publications: 8 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 undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32338069-GA-G is Pathogenic according to our data. Variant chr13-32338069-GA-G is described in ClinVar as Pathogenic. ClinVar VariationId is 37855.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.3717delA	p.Lys1239AsnfsTer20	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.3717delA	p.Lys1239AsnfsTer20	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.3348delA	p.Lys1116AsnfsTer20	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.3717delA		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459360 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 725712

African (AFR) AF: 0.00 AC: 0 AN: 33362

American (AMR) AF: 0.00 AC: 0 AN: 44352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 85672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110962

Other (OTH) AF: 0.00 AC: 0 AN: 60256

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5

May 01, 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 27, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The BRCA2 c.3717del (p.Lys1239Asnfs*20) variant, also published as 3945delA, has been reported in several individuals and families affected with hereditary breast and ovarian cancer (Breast Cancer Association Consortium, PMID: 33471991; Lubinski J et al., PMID: 15131399; Rebbeck TR et al., PMID: 29446198; Tai YC et al., PMID: 18042939; Tchou J et al., PMID: 17592676). This variant has been reported in the ClinVar database as a germline pathogenic variant by several submitters and is absent from the general population (gnomAD v.2.1.1), indicating it is not a common variant. This variant causes a frameshift by deleting a single nucleotide, leading to a premature termination codon, which is predicted to lead to nonsense mediated decay. Based on available information and the ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), this variant is classified as pathogenic. -

May 29, 2002

Breast Cancer Information Core (BIC) (BRCA2)

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:3

Sep 15, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with a personal and/or family history of breast cancer (PMID: 33471991 (2021), 17592676 (2007), 18042939 (2007), and 15131399 (2004)). Based on the available information, this variant is classified as pathogenic. -

Feb 28, 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 3945delA; This variant is associated with the following publications: (PMID: 15131399, 25673166, 18042939, 19620486, 17592676, 29446198, 32918181, 30787465, 33087929, 31892343, 31853058) -

Oct 17, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:3

Nov 24, 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.Lys1239Asnfs*20) 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, ovarian cancers (PMID: 15131399, 18042939). This variant is also known as 3945delA. ClinVar contains an entry for this variant (Variation ID: 37855). For these reasons, this variant has been classified as Pathogenic. -

Jan 31, 2014

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Oct 14, 2019

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Lys1239AsnfsX20 variant in BRCA2 (also referred to in the literature as c.3745delA) has been reported in at least 10 individuals with breast cancer and segregated with disease in at least 15 affected individuals from 2 families (Tchou 2007, Tai 2007, BIC database). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1239 and leads to a premature termination codon 20 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sept 8 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 37855). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PP1_Strong, PM2. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Nov 01, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3717delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 3717, causing a translational frameshift with a predicted alternate stop codon (p.K1239Nfs*20). This mutation has been detected in multiple families with female breast cancer, male breast cancer, and/or ovarian cancer (Lubinski J et al. Fam. Cancer. 2004;3(1):1-10; Tchou J et al. Clin. Breast Cancer 2007 Jun;7:627-33; Tai YC et al. J. Natl. Cancer Inst. 2007 Dec 5;99(23):1811-4). Of note, this alteration is also designated as 3945delA 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. -

Dec 05, 2022

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 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 detected in at least five individuals affected with breast cancer and in four suspected hereditary breast and ovarian cancer families (PMID: 15131399, 16912212, 17592676, 25673166, 33471991; Leiden Open Variation Database DB-ID BRCA2_004530; Color internal data). 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. -

Familial cancer of breast Pathogenic:1

Feb 23, 2017

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.1
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs80359401; hg19: chr13-32912206;