rs276174868

Positions:

• chr13-32340621-AGCA-AC

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.6267_6269delinsC​(p.Glu2089AspfsTer2) 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. E2089E) has been classified as Likely benign. 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:16
• Conservation: PhyloP100: -0.180

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 13-32340622-GCA-C is Pathogenic according to our data. Variant chr13-32340622-GCA-C is described in ClinVar as [Pathogenic]. Clinvar id is 38029.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.6267_6269delinsC	p.Glu2089AspfsTer2	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.6267_6269delinsC	p.Glu2089AspfsTer2	frameshift_variant	11/27	5	NM_000059.4	A2

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:16

Revision: reviewed by expert panel

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	BRCAlab, Lund University	Mar 02, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The BRCA2 p.Glu2089Aspfs*2 variant was identified in 12 of 81348 proband chromosomes (frequency: 0.0002) from individuals or families with breast cancer (Rebbeck 2018, Susswein 2015, Tung 2016, Wojcik 2016, Wong 2015). The variant was also identified in dbSNP (ID: rs276174868) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, Ambry Genetics and seven other submitters), LOVD 3.0 (7x as pathogenic), and in UMD-LSDB (2x as causal). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.6267_6269delinsC variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2089 and leads to a premature stop codon at position 2090. 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 BRCA2 associated cancers 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. -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 16, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 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 6495_6497delGCAinsC; Observed in individuals with BRCA2-related cancers (Vehmanen et al., 1997; Kwiatkowska et al., 2001; Wojcik et al., 2016); This variant is associated with the following publications: (PMID: 9150152, 26681312, 29164420, 26843898, 11139248, 29084914, 26976419, 25682074, 11102986, 35382848, 30040829, 30322717, 32438681, 29446198, 33471991, 32210335) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 20, 2023	The BRCA2 c.6267_6269delinsC (p.Glu2089Aspfs*2) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMIDs: 25682074 (2015), 26843898 (2016), 26976419 (2016), and 30322717 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Aug 10, 2021	This variant changes three nucleotides in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional studies have not been reported for this variant. This variant has been detected in at least six individuals affected with breast cancer and additional hereditary breast cancer families (PMID: 9150152, 11102986, 11139248, 25682074, 26681312, 26843898, 26976419, 33471991; Leiden Open Variation Database DB-ID BRCA2_003068; Color internal data) and one individual affected with breast and/or ovarian cancer (PMID: 32438681). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 21, 2021	The c.6267_6269delGCAinsC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from the deletion of 3 nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.E2089Dfs*2). This mutation has been observed in numerous hereditary breast and ovarian cancer (HBOC) families whose histories included early onset breast cancer, ovarian cancer, male breast cancer and/or triple negative breast cancer (Vehmanen P et al. Am. J. Hum. Genet. 1997 May;60:1050-8; Kiechle M et al. Hum. Mutat. 2000 Dec;16:529-30; Kwiatkowska E et al. Hum. Mutat. 2001;17:73; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Wojcik P et al. Hered Cancer Clin Pract. 2016 Feb;14:5; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Nilsson MP et al. Breast Cancer Res Treat, 2018 Feb;168:117-126; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 6495G>C + 6496delCA, 6495delGCAinsC and 6495del3insC in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2020	Variant summary: BRCA2 c.6267_6269delinsC (p.Glu2089AspfsX2) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 244786 control chromosomes. c.6267_6269delinsC has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 03, 2023	This sequence change creates a premature translational stop signal (p.Glu2089Aspfs*2) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 9150152, 25682074, 26681312, 26843898, 26976419, 30322717). This variant is also known as 6495G>C, 6496delCA. For these reasons, this variant has been classified as Pathogenic. -

BRCA2-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 27, 2023

The BRCA2 c.6267_6269delinsC variant is predicted to result in a frameshift and premature protein termination (p.Glu2089Aspfs*2). This variant has been reported to be causative for breast cancer (See for example - Vehmanen et al. 1997. PubMed ID: 9150152; Kwiatkowska et al. 2001. PubMed ID: 11139248; Wong-Brown et al. 2015. PubMed ID: 25682074; Susswein et al. 2015. PubMed ID: 26681312, Table S1; Wojcik et al. 2016. PubMed ID: 26843898; Tung et al. 2016. PubMed ID: 26976419). This variant has not been reported in ClinVar or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Familial cancer of breast Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 04, 2023

- -

Ovarian neoplasm Pathogenic:1

Pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs276174868; hg19: chr13-32914759;