rs80359343
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.26delC(p.Pro9GlnfsTer16) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,782 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. P9P) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.26delC | p.Pro9GlnfsTer16 | frameshift_variant | Exon 2 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893 | c.-340delC | 5_prime_UTR_variant | Exon 2 of 27 | 1 | ENSP00000499438.2 | ||||
| BRCA2 | ENST00000614259.2 | n.26delC | non_coding_transcript_exon_variant | Exon 1 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461782Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727190
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6
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Variant allele predicted to encode a truncated non-functional protein. -
not provided Pathogenic:3
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The BRCA2 c.26del (p.Pro9Glnfs*16) 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 and families with breast and/or ovarian cancer (PMIDs: 33758026 (2022), 34657373 (2022), 33471991 (2021), 31263054 (2019), 29446198 (2018), 28888541 (2017), 27376475 (2016), 23028338 (2012), 22711857 (2012), 11044354 (2000), 8988179 (1997), 3413277 (1988)), including male breast cancer (PMIDs: 17636422 (2008), 11879560 (2002)). Additionally, this variant was seen in individuals with prostate cancer (PMID: 27433846 (2016)) and pancreatic cancer (PMIDs: 32073954 (2020), 29922827 (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. -
Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Gayther et al., 1997; Basham et al., 2002; Evans et al., 2008; Tutt et al., 2010; Alsop et al., 2012; Thompson et al., 2012; Frugtniet et al., 2022); 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; 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 252delC, 253delC, and 254delC; This variant is associated with the following publications: (PMID: 22711857, 21702907, 14662532, 15131399, 31263054, 8988179, 12036913, 27376475, 23028338, 11879560, 20609467, 17636422, 11044354, 18158280, 27433846, 30787465, 28888541, 32778766, 29922827, 33758026, 34657373) -
Hereditary cancer-predisposing syndrome Pathogenic:3
The c.26delC pathogenic mutation, located in coding exon 1 of the BRCA2 gene, results from a deletion of one nucleotide at position 26, causing a translational frameshift with a predicted alternate stop codon (p.P9Qfs*16). This mutation has been identified in multiple individuals with breast, ovarian, prostate, and/or pancreatic cancers (Gayther SA et al. Nat. Genet. 1997 Jan;15(1):103-5; Evans DG et al. Fam. Cancer 2008 Jul;7(2):113-7; Alsop K et al. J. Clin. Oncol. 2012 Jul;30(21):2654-63; Thompson ER et al. PLoS Genet. 2012 Sep;8(9):e1002894; Pritchard CC et al. N. Engl. J. Med. 2016 Aug 4;375(5):443-53; Schenkel LC et al. J. Mol. Diagn. 2016 09;18(5):657-667; Hu C et al. JAMA 2018 06;319(23):2401-2409). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620). Of note, this alteration is also designated as 254delC and 253delC 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. -
This variant deletes 1 nucleotide in exon 2 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 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. -
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Hereditary breast ovarian cancer syndrome Pathogenic:3
This sequence change creates a premature translational stop signal (p.Pro9Glnfs*16) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 8988179, 11044354, 17636422, 22711857, 23028338). It has also been observed to segregate with disease in related individuals. This variant is also known as 253delC. ClinVar contains an entry for this variant (Variation ID: 51330). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: BRCA2 c.26delC (p.Pro9GlnfsX16) 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 251392 control chromosomes. c.26delC has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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Breast and/or ovarian cancer Pathogenic:1
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Inherited breast cancer and ovarian cancer Pathogenic:1
PVS1,PM5_Strong -
BRCA2-related disorder Pathogenic:1
The BRCA2 c.26delC variant is predicted to result in a frameshift and premature protein termination (p.Pro9Glnfs*16). This variant has been reported in individuals with hereditary breast and ovarian cancer (Referred to as 253delC in Gayther et al. 1997. PubMed ID: 8988179; Petridis et al. 2019. PubMed ID: 31263054) and in one male patient with metastatic prostate cancer (Pritchard et al. 2016. PubMed ID: 27433846). This variant has not been reported in a large population database and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51330/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Malignant tumor of breast Pathogenic:1
The p.Pro9GlnfsX16 deletion variant was identified in 4 of 3028 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Alsop 2012, Gayther 1997, Weitzel 2003).The variant was also identified in dbSNP (ID: rs80359343) “With pathogenic allele”, HGMD, LOVD, UMD (1X as a causal variant), and the BIC database (7X as clinically important). The p.Pro9GlnfsX16 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 9 and leads to a premature stop codon 16 codons downstream. 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at