ClinVar Genomic variation as it relates to human health

Variant allele predicted to encode a truncated non-functional protein.

This c.7069_7070delCT (p.Leu2357Valfs*2) frameshift variant in the BRCA2 gene is predicted to introduce a premature translation termination codon. It has been reported in multiple unrelated patients and families affected with breast cancer [PMID 9429140, 18465347, 21120943, 21324516, 24504028] and is extremely rare in general population. Therefore, this variant in the BRCA2 gene is classified as pathogenic.

Observed in multiple individuals with BRCA2-related cancers (Garvin 1997, Zhang 2011, Cunningham 2014, Song 2014, Ellingson 2015, Decker 2016, Afghahi 2017); 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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26745875, 24728189, 26681312, 26296701, 29084914, 9429140, 21324516, 24830819, 20104584, 21120943, 27087322, 24504028, 28166811, 28087643, 27978560, 29339979, 30720243, 30322717, 31432501, 31447099, 31263571, 31948886, 32853339, 30787465, 33087929)

PVS1; PM5_PTC_Strong

The p.Leu2357ValfsX2 variant in BRCA2 has been identified in >30 individuals with BRCA2-associated cancers (Garvin 1997, Spearman 2008, Borg 2010, Caux-Moncoutier 2011, Zhang 2011, Breast Cancer Information Core (BIC) database). This variant has also been identified in 7/12892 European chromosomes by the Genome Aggregation Database (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 2357 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in individuals with HBOC. In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282439.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP Criteria applied: PVS1, PS4, PM2.

This variant deletes 2 nucleotides in exon 14 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 7297delCT in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals affected with breast and/or ovarian cancer (PMID: 9667259, 16234499, 18824701, 20104584, 21324516, 21913181, 24504028, 24549055, 24728189), as well as colorectal cancer (PMID: 27978560) and high grade prostate cancer (PMID: 34700141). This variant has been identified in 7/282332 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 BRCA2 c.7069_7070del; p.Leu2357ValfsTer2 variant (rs80359636), also known as 7297delCT, has been reported in multiple individuals with early onset breast or ovarian cancer (Caux-Moncoutier 2011, Cunningham 2014, Garvin 1997, Zhang 2011). It is listed as pathogenic in ClinVar (Variation ID: 38082) and is observed 7 times in the Genome Aggregation Database (7/276,822 alleles). This variant causes a frameshift by deleting two nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the variant is considered to be pathogenic. References: Caux-Moncoutier V et al. EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients. Hum Mutat. 2011; 32(3):325-34. PMID: 21120943. Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014; 4:4026. PMID: 24504028. Garvin A et al. BRCA1 and BRCA2 mutation analysis in 86 early onset breast/ovarian cancer patients. J Med Genet. 1997; 34(12):990-5. PMID: 9429140. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011; 121(2):353-7. PMID: 21324516.

Variant summary: The BRCA2 c.7069_7070delCT (p.Leu2357Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g., c.7133C>G [p.Ser2378X], c.7180A>T [p.Arg2394X], and c.7360delA [p.Ile2454fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.000033 (4/121100 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been identified in numerous patients in published reports (e.g., Thomassen_Acta Oncol_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

This 6 year old male with global developmental delays (at-risk for mild intellectual disability), ADHD, disruptive behavior, and mild overgrowth was found to carry a maternally inherited 2 bp deletion in the BRCA2 gene. The c.7069_7070delCT pathogenic variant in the BRCA2 gene, previously reported as 7297delCT using alternate nomenclature, has been published in association with early-onset breast cancer, ovarian cancer, and prostate cancer (Garvin et al., 1997; Zhang et al., 2011; Cunningham et al., 2014; Song et al., 2014; Ellingson et al., 2015; Decker et al., 2016). The deletion causes a frameshift and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Given that this is an adult-onset condition, the patient is not expected to be affected at this time. The patient's mother has not been formally evaluated in the oncology setting, so her current status is unknown.

Criteria applied: PVS1,PS4,PM5_STR

This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000054 (7/128928 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 9429140 (1997)), ovarian cancer (PMID: 29084914 (2018), 30322717 (2018), 31263571 (2019)), colorectal cancer (PMID: 27978560 (2016)), and pancreatic cancer (PMID: 31948886 (2020), 32853339 (2021)). Based on the available information, this variant is classified as pathogenic.

PP5, PM2, PVS1

This sequence change creates a premature translational stop signal (p.Leu2357Valfs*2) 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 (rs756538291, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 9429140, 21324516, 24504028, 24728189). This variant is also known as 7297delCT. ClinVar contains an entry for this variant (Variation ID: 38082). For these reasons, this variant has been classified as Pathogenic.

Criteria applied: PVS1,PM5_STR

This variant deletes 2 nucleotides in exon 14 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 7297delCT in the literature according to the BIC nomenclature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in over ten individuals affected with breast and/or ovarian cancer (PMID: 9667259, 16234499, 18824701, 20104584, 21324516, 21913181, 24504028, 24549055, 24728189), as well as colorectal cancer (PMID: 27978560) and high grade prostate cancer (PMID: 34700141). This variant has been identified in 7/282332 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.7069_7070delCT pathogenic mutation, located in coding exon 13 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 7069 to 7070, causing a translational frameshift with a predicted alternate stop codon (p.L2357Vfs*2). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) cohorts (Garvin AM et al. J. Med. Genet. 1997 Dec;34:990-5; Thomassen M et al. Acta Oncol. 2008;47:772-7; Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Litton JK et al. Cancer. 2012 Jan;118:321-5; Chong HK et al. PLoS ONE, 2014 May;9:e97408; Song H et al. Hum Mol Genet, 2014 Sep;23:4703-9; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24:326-333; Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3; Bertelsen B et al. NPJ Genom Med, 2019 Jun;4:13). This mutation has also been reported in prostate and pancreatic cancer cohorts (Schwartz M et al. Clin Genet, 2019 12;96:579-584; Boyle JL et al. JCO Precis Oncol, 2020 Mar;4; Moses M et al. Oncotarget, 2020 Jan;11:15-21). Of note, this alteration is also designated as 7297delCT 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.

The BRCA2 c.7069_7070delCT variant is predicted to result in a frameshift and premature protein termination (p.Leu2357Valfs*2). This variant has been reported to be causative for hereditary cancer such as breast, ovarian, or colorectal cancers (reported as 7297delCT in Garvin et al. 1997. PubMed ID: 9429140; eTable 3, Pearlman et al. 2017. PubMed ID: 27978560; Table S3, Labidi-Galy et al. 2018. PubMed ID: 29084914; Heramb et al. 2018. PubMed ID: 29339979). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38082/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.

The BRCA2 p.Leu2357ValfsX2 variant was identified in 2 of 2856 proband chromosomes (frequency: 0.001) from individuals or families with Breast and/or Ovarian cancer (Garvin, 1997; Zhang, 2011). The variant was also identified in dbSNP (ID: rs80359636) “With pathogenic allele”, HGMD, LOVD, ClinVar database, the BIC database (31X with Important clinical importance), and UMD (34X as a class 5-causal variant). The variant was classified as a pathogenic variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The p.Leu2357ValfsX2 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2357 and leads to a premature stop codon 2 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.