rs730881619

Positions:

• chr13-32398403-C-CATTT

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000059.4(BRCA2):​c.9891_9894dup​(p.Gln3299IlefsTer29) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,206 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. A3297A) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: BRCA2 NM_000059.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: -1.01

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 14 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 15 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-32398403-C-CATTT is Pathogenic according to our data. Variant chr13-32398403-C-CATTT is described in ClinVar as [Pathogenic]. Clinvar id is 182326.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.9891_9894dup	p.Gln3299IlefsTer29	frameshift_variant	27/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8	c.9891_9894dup	p.Gln3299IlefsTer29	frameshift_variant	27/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251220 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135768

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2022	Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Observed in individuals with prostate cancer (Matejcic 2020); 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 10119_10122dup; This variant is associated with the following publications: (PMID: 9126738, 30787465, 32832836, 29922827) -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Dec 04, 2018	DNA sequence analysis of the BRCA2 gene demonstrated a 4 base pair deletion in exon 27, c.9891_9894dup. This sequence change results in an amino acid frameshift and creates a premature stop codon 28 amino acids downstream of the mutation, p.Gln3299Ilefs*29. This pathogenic sequence change is predicted to result in the production of a truncated BRCA2 protein with potentially abnormal function. While this particular variant has not been previously reported in the literature, loss-of-function variants in BRCA2 have been described in patients with breast and/or ovarian cancer. -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 25, 2018	- -

Familial cancer of breast Pathogenic:2

Pathogenic, flagged submission	clinical testing	GeneDx	Dec 13, 2013	This variant is denoted BRCA2 c.9894_9895insATTT (aka c.9891_9894dupATTT) at the cDNA level and p.Gln3299IlefsX29 (Q3299IfsX29) at the protein level. The normal sequence with the bases that are duplicated in brackets is AGGC{ATTT}CAGC. The duplication causes a frameshift, changing a Glutamine to an Isoleucine at codon 3299, and creating a premature stop codon at position 29 of the new reading frame. This mutation is predicted to cause loss of normal protein function through protein truncation. Although this mutation has not been previously reported to our knowledge, it is considered pathogenic and is indicative of Hereditary Breast and Ovarian Cancer (HBOC) syndrome, an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers. The predominant BRCA2-related cancer risks for women who have not been diagnosed with cancer have been estimated as 41% - 84% lifetime risk for breast cancer and 11% - 27% lifetime risk for ovarian cancer (Ford 1998, Risch 2006). BRCA2 mutations have also been reported in women with fallopian tube carcinoma, primary peritoneal carcinoma, and uterine serous carcinoma (Levine 2003, Biron-Shental 2006). Women with BRCA1/2 mutations also have an increased risk for contralateral breast cancer. Women with BRCA mutations whose first cancer was diagnosed under age 40 have a 21-31% risk to develop a second breast cancer within 10 years and a 63% risk to develop a second breast cancer within 25 years. Women with BRCA mutations whose first cancer was diagnosed between ages 40 and 50 have an 11-13% risk to develop a second breast cancer within 10 years and a 44-49% risk within 25 years. Women with BRCA mutations whose first cancer was diagnosed after age 50 have an 8% risk to develop a second breast cancer within 10 years and a 20% risk within 25 years (Graeser 2009). Other cancer risks associated with a BRCA2 mutation include up to a 7% risk for pancreatic cancer (Ozcelik 1997, The Breast Cancer Linkage Consortium 1999), up to a 34% risk for prostate cancer in male carriers (Thompson 2001), and up to a 7% risk for male breast cancer (Liede 2004). The variant is found in BRCA1-BRCA2 panel(s). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 02, 2022	- -

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

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. -

Fanconi anemia complementation group D1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Jul 13, 2023

PVS1, PM2, PS4_supporting -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2024

The c.9891_9894dupATTT pathogenic mutation, located in coding exon 26 of the BRCA2 gene, results from a duplication of ATTT at nucleotide positions 9891 to 9894, causing a translational frameshift with a predicted alternate stop codon (p.Q3299Ifs*29). This alteration occurs at the 3' terminus of theBRCA2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 3.5% of the protein. However, premature stop codons are typically deleterious in nature, and the impacted region is critical for protein function (Ambry internal data). This mutation alters the last 29 amino acids of the RAD51 binding region of the native BRCA2 protein. One study previously reported the importance of this region in the interaction between BRCA2 and RAD51 proteins during recombination-mediated DNA repair function (Davies et al. Nat. Struct. Mol. Biol. 2007 Jun 14(6):475–483). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Hereditary breast ovarian cancer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 01, 2023

This sequence change creates a premature translational stop signal (p.Gln3299Ilefs*29) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 120 amino acid(s) of the BRCA2 protein. This variant is present in population databases (rs756361508, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with BRCA2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 182326). 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. -

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: rs730881619; hg19: chr13-32972540;