rs80359460
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.4631delA(p.Asn1544ThrfsTer24) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.4631delA | p.Asn1544ThrfsTer24 | frameshift_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.4262delA | p.Asn1421ThrfsTer24 | frameshift_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.4631delA | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250170Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135478
GnomAD4 exome AF: 0.00000411 AC: 6AN: 1461216Hom.: 0 Cov.: 44 AF XY: 0.00000550 AC XY: 4AN XY: 726910
GnomAD4 genome 0.0000131 AC: 2AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74316
ClinVar
Submissions by phenotype
not provided Pathogenic:7
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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; Observed in individuals with BRCA2-related cancers, and has been described as a recurrent variant in the Filipino population (Risch 2001, De Leon-Matsuda 2002, Zhang 2011); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4859delA; This variant is associated with the following publications: (PMID: 26681312, 18779604, 10498392, 30720243, 21324516, 11179017, 17591843, 11920621, 28454591, 26187060, 23364291, 17148771, 30322717, 31372034, 29625052, 31887429) -
This variant is a single base pair deletion at amino acid residue 1544 of the BRCA2 gene. It results in a frame-shift creating a new stop codon after 24 amino acids, thus resulting in a truncated protein. This mutation has been described in international bibliography (http://research.nhgri.nih.gov/projects/bic) as pathogenic. -
The BRCA2 c.4631delA, p.Asn1544ThrfsTer24 variant (rs80359461), also known as 4859delA and 4856delA, is reported in multiple patients with hereditary breast and ovarian cancer syndrome (see Ashour 2019, Carter 2018, Hopper 1999, Lilyquist 2017, Zhang 2011). This variant is also reported in ClinVar (Variation ID: 37913). It is only found on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Ashour M et al. Ezzat Shafik H. Frequency of germline mutations in BRCA1 and BRCA2 in ovarian cancer patients and their effect on treatment outcome. Cancer Manag Res. 2019 Jul 8;11:6275-6284. PMID: 31372034. Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Hopper JL et al. Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2. Australian Breast Cancer Family Study. Cancer Epidemiol Biomarkers Prev. 1999 Sep;8(9):741-7. PMID: 10498392. Lilyquist J et al. Frequency of mutations in a large series of clinically ascertained ovarian cancer cases tested on multi-gene panels compared to reference controls. Gynecol Oncol. 2017 Nov;147(2):375-380. PMID: 28888541. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. PMID: 21324516. -
The BRCA2 p.Asn1544Thrfs*24 variant was identified in 8 of 5746 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer and was not identified in 692 control chromosomes from healthy individuals (De Leon Matsuda 2002, Hopper 1999, Kurian 2008, Risch 2001, Zhang 2011). The variant was also identified in the following databases: dbSNP (ID: rs80359461) as “With Pathogenic allele”, ClinVar (10x as pathogenic, reviewed by expert panel), Clinvitae (8x as pathogenic, 1x as likely pathogenic and 1x as uncertain significance), and ARUP Laboratories (as definitely pathogenic). The variant was not identified in Cosmic, MutDB, LOVD 3.0, UMD-LSDB, BIC Database, or the Zhejiang Colon Cancer Database. The variant was also identified by our laboratory in 4 individuals with ovarian cancer. The variant is reported in the literature as a founder mutation in the Philippines (De Leon Matsuda 2002, Ferla 2007, Shanmughapriya 2013). The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016). The p.Asn1544Thrfs*24 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1544 and leads to a premature stop codon at position 1567. 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 hereditary breast and ovarian cancer 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. -
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The BRCA2 c.4631del (p.Asn1544Thrfs*24) 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 multiple individuals with hereditary breast and/or ovarian cancer (PMID: 10498392 (1999), 11179017 (2001), 11920621 (2002), 20807450 (2010), 21324516 (2011), 30322717 (2018), 31372034 (2019), 32885271 (2021)) and is described as a founder mutation in the Filipino population (PMID: 11920621 (2002), 17591843 (2007)). This variant was also seen in a reportedly healthy individual (PMID: 32719484 (2020)). The frequency of this variant in the general population, 0.000004 (1/250170 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6
The BRCA2 c.4631del p.(Asn1544ThrfsTer24) variant causes a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. Across a selection of the available literature, this variant, which is also described as c.4856delA and c.4859delA, has been reported in a heterozygous state in at least eight individuals with breast or ovarian cancer and has been shown to be a founder variant in the Philippines (PMID: 11920621; 21324516; 31372034; 11179017; 20807450). This variant is not observed at a significant frequency in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. This variant has been classified as pathogenic by multiple submitters in ClinVar, including the ENIGMA expert panel. Based on the available evidence, the c.4631del p.(Asn1544ThrfsTer24) variant is classified as pathogenic for hereditary breast and ovarian cancer. -
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Variant allele predicted to encode a truncated non-functional protein. -
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Hereditary breast ovarian cancer syndrome Pathogenic:5
The p.Asn1544ThrfsX24 variant in BRCA2 (also referred to in the literature as c.4859delA) is a founder variant in the Phillipines and has been reported in >20 individuals with BRCA2-related cancers (Hopper 1999, Zhang 2011, De Leon Matsuda 2002, BIC database). It has also been identified in 1/34418 Latino chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1544 and leads to a premature termination codon 24 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: 37913). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4. -
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This sequence change creates a premature translational stop signal (p.Asn1544Thrfs*24) 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 present in population databases (rs80359461, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer as well as non-Hodgkin's lymphoma (PMID: 10498392, 11920621, 17591843, 21324516). It is commonly reported in individuals of Filipino ancestry (PMID: 10498392, 11920621, 17591843, 21324516). This variant is also known as 4856delA and 4859delA. ClinVar contains an entry for this variant (Variation ID: 37913). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: The variant of interest causes a frameshift mutation resulting in a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest was observed in the large, broad control population, ExAC, 1/120458, although this observance needs to be cautiously considered due to the cohort harboring individuals with a phenotype that could harbor a BRCA2 mutation. The variant of interest has been reported in multiple affected individuals via publications, along with multiple reputable databases/clinical laboratories citing the variant as "pathogenic." Therefore, the variant of interest is classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 10498392, 11920621, 17148771, 21324516, 26681312, 27153395, 30430080). This variant has been identified in 1/250170 chromosomes 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. -
The c.4631delA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 4631, causing a translational frameshift with a predicted alternate stop codon (p.N1544Tfs*24). This variant has been reported in multiple breast and/or ovarian cancer families (Hopper JL et al. Cancer Epidemiol. Biomarkers Prev. 1999 Sep;8:741-7; Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; De Leon Matsuda ML et al. Int. J. Cancer. 2002 Apr;98:596-603; Kurian AW et al. J. Clin. Oncol. 2008 Oct;26:4752-8; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7). In addition, it has been described as a founder pathogenic mutation in the Philippines (De Leon Matsuda ML et al. Int. J. Cancer, 2002 Apr;98:596-603). Of note, this alteration is also designated as 4856delA and 4859delA 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. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Criteria applied: PVS1,PM5_STR -
BRCA2-related cancer predisposition Pathogenic:1
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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 10498392, 11920621, 17148771, 21324516, 26681312, 27153395, 30430080). This variant has been identified in 1/250170 chromosomes 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. -
BRCA2-related disorder Pathogenic:1
The BRCA2 c.4631delA variant is predicted to result in a frameshift and premature protein termination (p.Asn1544Thrfs*24). This variant has been reported in several individuals with breast and ovarian cancer and is considered a possible founder mutation in individuals of Filipino ancestry (reported as 4856delA in Hopper et al. 1999. PubMed ID: 10498392; reported as 4859delA in Zhang et al. 2011. PubMed ID: 21324516 and De Leon Matsuda et al. 2002. PubMed ID: 11920621). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD and is documented as pathogenic by several laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37913/). Frameshift variants in BRCA2 are expected to be pathogenic. In summary, this variant is interpreted as pathogenic. -
Familial cancer of breast Pathogenic:1
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Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1 Other:1
Variant reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 3/8/2018 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at