13-32363367-C-G
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000059.4(BRCA2):c.8165C>G(p.Thr2722Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2722I) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000059.4 missense
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 18 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.8165C>G | p.Thr2722Arg | missense_variant | Exon 18 of 27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.8165C>G | p.Thr2722Arg | missense_variant | Exon 18 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.7796C>G | p.Thr2599Arg | missense_variant | Exon 18 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.*223C>G | non_coding_transcript_exon_variant | Exon 17 of 26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000614259.2 | n.*223C>G | 3_prime_UTR_variant | Exon 17 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6Uncertain:2
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PM2_Supporting; PP1; PS3; Expert panel -
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IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 -
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not provided Pathogenic:5
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Multifactorial studies suggest this variant is associated with hereditary breast and ovarian cancer (PMID: 17924331, 21990134); Published functional studies of the p.(T2722R) missense variant demonstrate a damaging effect: impaired homology-directed repair activity, increased centrosome amplification, inability to rescue cell growth, PARP inhibitor sensitivity (PMID: 23108138, 18451181, 18607349, 29988080, 29884841, 32444794); RNA studies demonstrate exon skipping, but studies quantifying the amount of mutant and wild-type transcripts found the full length wild-type transcript to be more abundant (PMID: 12145750, 18607349, 20215541); Observed in families with hereditary breast/ovarian cancer and reported to segregate with disease in at least one kindred (PMID: 12145750, 16683254, 28324225); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8393C>G; This variant is associated with the following publications: (PMID: 24323938, 29394989, 33754277, 29446198, 19043619, 25146914, 17924331, 12145750, 18451181, 18607349, 20215541, 16683254, 16211554, 28324225, 22962691, 18424508, 17899372, 23893897, 30696104, 29988080, 29884841, 32444794, 28339459, 33964450, 35736817, 31907386, 33609447, 35665744, 37713444, 34906479, 35464868, 27878467, 33978741, 36471068, 37719058, 36061650, 37528630, 23108138, 21990134, 12228710) -
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Hereditary cancer-predisposing syndrome Pathogenic:3
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The p.T2722R pathogenic mutation (also known as c.8165C>G), located in coding exon 17 of the BRCA2 gene, results from a C to G substitution at nucleotide position 8165. The threonine at codon 2722 is replaced by arginine, an amino acid with similar properties. This alteration has been reported in a 38-year breast cancer patient, her affected sister and their affected mother (Fackenthal J et al. Am J Hum Genet. 2002 Sep;71(3):625-31). This same study also demonstrated that this alteration results in decreased protein function and incomplete skipping of exon 18, which was corroborated by several other functional studies (Fackenthal J et al. Am J Hum Genet. 2002 Sep;71(3):625-31, Farrugia D et al. Cancer Res. 2008 May 1;68(9):3523-31, Kuznetsov S et al. Nat Med. 2008 Aug;14(8):875-81, Sanz D et al. Clin Cancer Res. 2010 Mar 15;16(6):1957-67, Guidugli L et al. Cancer Res. 2013 Jan 1;73(1):265-75). Additionally, a homology-directed DNA repair (HDR) assay demonstrated p.T2722R to have low functionality, with a probability of pathogenicity of 0.99 (Guidugli L et al. Am. J. Hum. Genet. 2018 Feb;102(2):233-248). In addition, this alteration is located in the highly conserved oligonucleotide binding domain (Karchin R et al Cancer Inform. 2008;6:203-16). This alteration has been classified as pathogenic (p>0.9975) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8). Of note, this alteration is also designated as 8393C>G in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation. -
This missense variant replaces threonine with arginine at codon 2722 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). RNA studies found that this variant causes partial exon 18 skipping both in patient-derived RNA (PMID: 18607349, 12145750) and in a minigene splicing assay (PMID: 20215541). Functional studies reported the full-length variant protein to be defective in homology-directed DNA repair, centrosome duplication and BRCA2-null mouse embryonic cell complementation assays (PMID: 18451181, 18607349, 23108138, 25146914, 33609447, 35736817). This variant has been observed in several individuals with a personal and/or family history of breast/ovarian cancer (PMID: 12145750, 16683254, 18451181, 25682074, 28324225, 29446198, 30039884, 31407530, 35464868). In a large breast cancer case-control meta-analysis conducted by the BRIDGES consortium, this variant was reported in 5/60466 cases and 1/53461 unaffected controls (OR=4.421 (95%CI 0.516 to 37.844))(PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000289). This variant has also been reported in multifactorial analysis as pathogenic (PMID: 18451181, 23108138) based in part on co-segregation and family history likelihood ratios of 10.8 and 6.95, respectively (PMID: 18451181, 23108138). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:3
This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 2722 of the BRCA2 protein (p.Thr2722Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12145750). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 9340). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 33609447) indicates that this missense variant is expected to disrupt BRCA2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 18451181, 18607349, 23108138, 25146914). Studies have shown that this missense change is associated with inconclusive levels of altered splicing (PMID: 12145750, 18607349; internal data). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: BRCA2 c.8165C>G (p.Thr2722Arg) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing by a disruption of ESE sites. At least one publication reports experimental evidence confirming these computational in-silico splicing predictions that this variant results in exon skipping leading to an out of frame fusion of BRCA2 exons 17 and 19 (Fackenthal_2002). This has been additionally corroborated by an HDR assay reporting loss of activity confirming an experimental impact on protein function (Guidugli_2018). The variant was absent in 251098 control chromosomes. c.8165C>G has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Fackenthal_2002, Meisel_2017, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories and one expert panel (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic (n=5 to include the expert panel)/likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
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Familial cancer of breast Pathogenic:2
Criteria applied: PVS1,PM5_STR,PM2_SUP, PP4_STR -
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BRCA2-related disorder Pathogenic:1
The BRCA2 c.8165C>G (p.Thr2722Arg) variant has been reported in three studies in which it is found in a heterozygous state in a mother and her two daughters, all of whom were diagnosed with early onset breast and/or ovarian cancer, in a heterozygous state in two individuals with breast cancer and a risk family profile indicative of HBOC or family history of breast cancer (Fackenthal et al. 2002; van der Hout et al. 2006; Meisel et al. 2017). Control data are unavailable for this variant, which, despite good coverage in the region, is also not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium or the Genome Aggregation Database. RT-PCR analysis of patient derived mRNA showed that the p.Thr2722Arg variant resulted in skipping of exon 18 which produced a shorter transcript than wild type that was predicted to cause a premature truncation of the BRCA2 protein (Fackenthal et al. 2002). In a subsequent study the full length wild type transcript was shown to be more abundant (Kuznetsov 2008). The p.Thr2722Arg variant protein demonstrated impaired BRCA2 protein function in a homology-directed DNA break repair assay as well as an embryonic stem cell based survival assay (Guidugli et al. 2014; Hendriks et al. 2014). Kuznetsov et al. (2008) demonstrated that the variant failed to rescue mouse ES-cell lethality. In addition, a different variant at the same nucleotide position resulting in a different amino acid change was reported in an individual with breast cancer and classified as likely pathogenic (Yadav et al. 2016). Based on the collective evidence, the p.Thr2722Arg variant is classified as likely pathogenic for hereditary breast and ovarian cancer. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at