rs276174843
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.4163_4164delCTinsA(p.Thr1388AsnfsTer22) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift, missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.4163_4164delCTinsA | p.Thr1388AsnfsTer22 | frameshift_variant, missense_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.3794_3795delCTinsA | p.Thr1265AsnfsTer22 | frameshift_variant, missense_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.4163_4164delCTinsA | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5
- -
- -
The BRCA2 p.Thr1388Asnfs*22 variant was identified in 22 of 59572 proband chromosomes (frequency: 0.0004) from individuals or families with HBOC (Rebbeck 2018). The variant was also identified in ClinVar (classified as pathogenic by ENIGMA expert panel, Invitae, GeneDX, Ambry Genetics, and seven other submitters) and LOVD 3.0 (7x). 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.4163_4164delinsA variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1388 and leads to a premature stop codon at position 1409. 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 (HBOC) 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. -
- -
Variant allele predicted to encode a truncated non-functional protein. -
Hereditary breast ovarian cancer syndrome Pathogenic:3
This sequence change creates a premature translational stop signal (p.Thr1388Asnfs*22) 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). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer, prostrate cancer, or breast hamartoma and lipoma (PMID: 10923033, 12698193, 23633455, 26681312, 29368341, 32853339). This variant is also known as c.4163_4164delCTinsA, c.4163delCTinsA, and 4391delCTinsA. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: BRCA2 c.4163_4164delinsA (p.Thr1388AsnfsX22) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 241566 control chromosomes. c.4163_4164delinsA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (eg. Kauff_2003, Ruark_2013, George_2013, Susswein_2015, Alsop_2012). These data indicate that the variant is very likely to be associated with disease. Seven 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. -
- -
not provided Pathogenic:2
Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (gnomAD); Also known as 4391_4392delCTinsA; 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 a personal or family history consistent with pathogenic variants in this gene (Kauff et al., 2003; Alsop et al., 2012; George et al., 2013; Flaum et al., 2022); This variant is associated with the following publications: (PMID: 12698193, 21702907, 26586665, 23633455, 23242139, 12655515, 22711857, 26681312, 27376475, 29368341, 32918181, 34887416, 32853339, 36169650) -
The BRCA2 c.4163_4164delinsA (p.Thr1388Asnfs*22) 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 individuals with breast and/or ovarian cancer (PMIDs: 26681312 (2015), 23633455 (2013), 12698193 (2003)), and prostate cancer (PMID: 29368341 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant deletes 2 nucleotides and insert a new 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. This variant has been reported in families and individuals affected with prostate cancer, breast cancer, and/or ovarian cancer (PMID: 12698193, 23633455, 29368341). This variant has not been identified 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.4163_4164delCTinsA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from the deletion of two nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.T1388Nfs*22). This mutation has been reported in multiple individuals diagnosed with breast, ovarian cancer, and/or prostate cancer (Scottish/Northern Irish BRCA1/BRCA2 Consortium. Br. J. Cancer 2003 Apr; 88(8):1256-62; Alsop K et al. J. Clin. Oncol. 2012 Jul; 30(21):2654-63; George J et al. Clin. Cancer Res. 2013 Jul; 19(13):3474-84; Isaacsson Velho P et al. Prostate 2018 Apr;78:401-407). Of note, this alteration is also designated as 4391delCTinsA in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Familial cancer of breast Pathogenic:1
- -
BRCA2-related disorder Other:1
Variant interpreted as Pathogenic and reported on 08-15-2018 by Lab 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