rs80359698

Positions:

• chr13-32363427-ATGGCAGACTGACAGT-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM4 PP3 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.8229_8243delCAGACTGACAGTTGG​(p.Arg2744_Gly2748del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: BRCA2 NM_000059.4 disruptive_inframe_deletion
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5 U:3
• Conservation: PhyloP100: 7.78

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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000059.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant 13-32363427-ATGGCAGACTGACAGT-A is Pathogenic according to our data. Variant chr13-32363427-ATGGCAGACTGACAGT-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52531.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BRCA2	NM_000059.4	c.8229_8243delCAGACTGACAGTTGG	p.Arg2744_Gly2748del	disruptive_inframe_deletion	18/27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BRCA2	ENST00000380152.8	c.8229_8243delCAGACTGACAGTTGG	p.Arg2744_Gly2748del	disruptive_inframe_deletion	18/27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7	c.7860_7874delCAGACTGACAGTTGG	p.Arg2621_Gly2625del	disruptive_inframe_deletion	18/27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2	n.*287_*301delCAGACTGACAGTTGG		non_coding_transcript_exon_variant	17/26	2		ENSP00000506251.1
BRCA2	ENST00000614259	n.*287_*301delCAGACTGACAGTTGG		3_prime_UTR_variant	17/25	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5 Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:1 Uncertain:1

Uncertain significance, flagged submission	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	May 11, 2015	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 03, 2021

This variant has been reported in multiple families with hereditary breast and/or ovarian cancer in the published literature (PMID: 14757868 (2004), 18284688 (2008), 29339979 (2018)). It was not found in a large general population data set (Genome Aggregation Database (http://gnomad.broadinstitute.org/)). The variant has been reported to segregate with disease, and tumor tissue from affected individuals showed loss of the wild type BRCA2 allele (PMID: 14757868 (2004)). The variant results in the in-frame deletion of five amino acids in the DNA/DSS1 binding domain of the BRCA2 protein, which has been characterized as evolutionarily highly conserved and functionally significant (PMID: 14757868 (2004)). Analysis of this variant using a bioinformatics tool for the prediction of the effect of amino acid changes on protein structure and function yielded the prediction that this variant is disease causing. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on BRCA2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites. Variant is located in potentially critical domain of the protein. Based on the available information, we predict that the variant is likely pathogenic. -

Familial cancer of breast Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 28, 2024

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2023

The c.8229_8243del15 variant (also known as p.R2744_G2748del) is located in coding exon 17 of the BRCA2 gene. This variant results from an in-frame CAGACTGACAGTTGG deletion at nucleotide positions 8229 to 8243. This results in the in-frame deletion of five amino acids at codons 2744 to 2748. This alteration (designated as 8457del15) was first reported in an ovarian cancer patient diagnosed at age 50 and was shown to segregate with disease in this family (Martinez SL et al. J Med Genet, 2004 Feb;41:e18). In a large, clinic-based BRCA1/2 testing cohort in Norway, this variant was detected in five families (Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3). This amino acid region is well conserved in available vertebrate species, and is part of the OB1 domain, a region that has been designated as critical for protein function (Ambry internal data). In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 10, 2023

This variant, c.8229_8243del, results in the deletion of 5 amino acid(s) of the BRCA2 protein (p.Arg2744_Gly2748del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of hereditary breast and ovarian cancer (PMID: 14757868, 29339979). This variant is also known as 8457del15. ClinVar contains an entry for this variant (Variation ID: 52531). RNA analysis performed to evaluate the impact of this variant on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Gly2748Asp) have been determined to be pathogenic (PMID: 15026808, 17924331, 22711857, 23108138, 23328489, 25146914). 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. -

not specified Uncertain:1

Uncertain significance, flagged submission

research

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

Jan 31, 2014

- -

Breast and/or ovarian cancer Uncertain:1

Uncertain significance, flagged submission

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jan 26, 2016

- -

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: rs80359698; hg19: chr13-32937564;