rs756361508
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.9891_9894dupATTT(p.Gln3299fs) 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 (★★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
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]
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ACMG classification
Classification made for transcript
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 9 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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
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BRCA2 | ENST00000380152.8 | c.9891_9894dupATTT | p.Gln3299fs | frameshift_variant | 27/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.9522_9525dupATTT | p.Gln3176fs | frameshift_variant | 27/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*1949_*1952dupATTT | non_coding_transcript_exon_variant | 26/26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259.2 | n.*1949_*1952dupATTT | 3_prime_UTR_variant | 26/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251220Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135768
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74360
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 25, 2018 | - - |
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. - |
Familial cancer of breast Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 02, 2022 | - - |
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). - |
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 | Sep 24, 2024 | The c.9891_9894dupATTT (p.Q3299Ifs*29) alteration, located in exon 27 (coding exon 26) of the BRCA2 gene, consists of a duplication of ATTT at position 9891, causing a translational frameshift with a predicted alternate stop codon after 29 amino acids. 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). Based on data from gnomAD, the c.9891_9894dupATTT allele has an overall frequency of 0.001% (2/282620) total alleles studied. The highest observed frequency was 0.008% (2/24964) of African alleles. 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, 2007). Based on the available evidence, this alteration is classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | 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
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