NM_000059.4:c.4415_4418delAGAA
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.4415_4418delAGAA(p.Lys1472ThrfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000165 in 1,457,966 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. K1472K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
- Fanconi anemia complementation group D1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
- pancreatic cancer, susceptibility to, 2Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- medulloblastomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | MANE Select | c.4415_4418delAGAA | p.Lys1472ThrfsTer6 | frameshift | Exon 11 of 27 | NP_000050.3 | ||
| BRCA2 | NM_001432077.1 | c.4415_4418delAGAA | p.Lys1472ThrfsTer6 | frameshift | Exon 11 of 27 | NP_001419006.1 | |||
| BRCA2 | NM_001406720.1 | c.4415_4418delAGAA | p.Lys1472ThrfsTer6 | frameshift | Exon 11 of 27 | NP_001393649.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | TSL:5 MANE Select | c.4415_4418delAGAA | p.Lys1472ThrfsTer6 | frameshift | Exon 11 of 27 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000544455.6 | TSL:1 | c.4415_4418delAGAA | p.Lys1472ThrfsTer6 | frameshift | Exon 11 of 27 | ENSP00000439902.1 | ||
| BRCA2 | ENST00000530893.7 | TSL:1 | c.4046_4049delAGAA | p.Lys1349ThrfsTer6 | frameshift | Exon 11 of 27 | ENSP00000499438.2 |
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00000402 AC: 1AN: 248584 AF XY: 0.00000744 show subpopulations
GnomAD4 exome AF: 0.0000165 AC: 24AN: 1457966Hom.: 0 AF XY: 0.0000193 AC XY: 14AN XY: 724540 show subpopulations
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6
Variant allele predicted to encode a truncated non-functional protein.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Hereditary breast ovarian cancer syndrome Pathogenic:5
This sequence change creates a premature translational stop signal (p.Lys1472Thrfs*6) 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 (rs748716604, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and breast and/or ovarian cancer (PMID: 15131399, 15918047, 24010542, 26681682, 28195393). ClinVar contains an entry for this variant (Variation ID: 37902). For these reasons, this variant has been classified as Pathogenic.
Variant summary: BRCA2 c.4415_4418delAGAA (p.Lys1472ThrfsX6) 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. The variant allele was found at a frequency of 4.1e-06 in 243794 control chromosomes (gnomAD and publications). c.4415_4418delAGAA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lubinski 2004, Pietschmann 2005, Konstantopoulou 2014, Eccles 2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
This variant is a deletion of 4 nucleotides in exon 11 of the BRCA2 mRNA c.(4415_4418del), causing a frameshift after codon 1472 and the creation of a premature translation stop signal 6 amino acid residues later, p.(Lys1472Thrfs*6). This is expected to result in an absent or disrupted protein product. Truncating variants in the BRCA2 gene are known to be pathogenic (PMID:20104584). This variant is present in population databases (rs397507333) and it has been observed in individuals with breast or/and ovarian cancer and colorectal cancer (PMID:15131399, 15918047, 24010542, 26681682, 28195393). ClinVar contains entries for this variant where is listed as pathogenic (VCV000037902.55). Based on the classification criteria set by the ACMG and AMP (PMID:25741868) this variant has been classified as pathogenic.
The p.Lys1472ThrfsX6 variant in BRCA2 has been reported in at least 5 individuals with BRCA2-related cancers (Hansen 2017, Li 2018, Pietschmann 2005, Konstantopoulou 2014). It has also been identified in 1/112594 European 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 1472 and leads to a premature termination codon 6 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: 37902). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate.
not provided Pathogenic:4
The BRCA2 p.Lys1472Thrfs*6 variant was identified in 6 of 2414 proband chromosomes (frequency: 0.002) from individuals or families with Lynch syndrome, breast, or ovarian cancer (Hansen 2017, Karami 2013, Konstantopoulou 2014, Lubinski 2004, Pietschmann 2005). The variant was also identified in dbSNP (ID: rs397507333) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, GeneDx and six other submitters), LOVD 3.0 (7x as pathogenic), and in ARUP Laboratories (as definitely pathogenic) databases. The variant was not identified in COGR, Cosmic, UMD-LSDB, BIC Database, or Zhejiang University databases. 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.4415_4418del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1472 and leads to a premature stop codon at position 1477. 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.
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 (Pietschmann et al., 2005; Konstantopoulou et al., 2014; Eccles et al., 2016; Ashour et al., 2019; Deng et al., 2019); 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 4643_4646del, 4643_4646delAGAA, 4643del4, or 4643delAGAA; This variant is associated with the following publications: (PMID: 26681682, 29922827, 34687993, 29752822, 30720243, 30972954, 31372034, 15918047, 24010542, 19877752, 19139771, 24312913, 15131399, 26295337, 28195393, 26109977, 26300996, 31825140, 33087929, 20104584, 33632156)
Familial cancer of breast Pathogenic:2
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.4415_4418delAGAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 4415 to 4418, causing a translational frameshift with a predicted alternate stop codon (p.K1472Tfs*6). This pathogenic mutation, also designated as 4643del4, is located in the ovarian cancer cluster region (OCCR) and has been reported in multiple families with HBOC related cancers (Lubinski J et al. Fam Cancer. 2004;3(1):1-10; Pietschmann A et al. J. Cancer Res. Clin. Oncol.2005 Aug;131(8):552-8; Karami F and Mehdipour P. Biomed Res Int. 2013;2013:928562). 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.
This variant deletes 4 nucleotides 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: 15918047, 24010542, 24312913, 26681682, 27153395) or colorectal cancer (PMID: 28195393). This variant has been identified in 1/248584 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.
Breast and/or ovarian cancer Pathogenic:1
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Criteria applied: PVS1,PM5_STR,PM2_SUP
Gastric cancer Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at