ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7007G>C (p.Arg2336Pro) (rs28897743)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045113 SCV000073126 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 2336 of the BRCA2 protein (p.Arg2336Pro). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and proline. This variant also falls at the last nucleotide of exon 13 of the BRCA2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (rs28897743, ExAC no frequency). This variant has been reported in individuals with breast and/or ovarian cancer and Fanconi anemia (PMID: 9150172, 22399190, 20960228, 21548014). This variant is also known as 7235G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 52241). Experimental studies have shown that this missense change causes skipping of exons 12 and 13 (PMID: 22505045). A different variant affecting this nucleotide, c.7007G>A (p.Arg2336His), has also been reported in patients with breast and/or ovarian cancer and causes skipping of exons 12 and 13 (PMID: 16792514, 20215541, 22505045), indicating that this nucleotide may be critical for normal RNA splicing. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000214499 SCV000276750 pathogenic Hereditary cancer-predisposing syndrome 2018-01-25 criteria provided, single submitter clinical testing The c.7007G>C pathogenic mutation (also known as p.R2336P), located in coding exon 12 of the BRCA2 gene, results from a G to C substitution at nucleotide position 7007. The arginine at codon 2336 is replaced by proline, an amino acid with dissimilar properties. This change occurs in the last base pair of coding exon 12, which makes it likely to have some effect on normal mRNA splicing. In one study, RT-PCR analysis performed on extracted lymphoblastoid cell lines showed that this mutation results in the skipping of exons 12 and 13 (Houdayer C et al. Hum. Mutat. 2012 Aug; 33(8):1228-38). In addition, this mutation was identified in a French family with four cases of female breast cancer (Serova-Sinilnikova OM et al. Am. J. Hum. Genet. 1997 May; 60(5):1236-9), as well as in two individuals who either had breast cancer, ovarian cancer, or were determined to be at a high risk (Laitman Y et al. Breast Cancer Res. Treat. 2011 Jun; 127(2):489-95; Sagi M et al. Fam. Cancer 2011 Mar; 10(1):59-63). This mutation has also been detected in conjunction with a nonsense mutation in BRCA2 in an individual with Fanconi anemia (Meng L et al. JAMA Pediatr. 2017 12;171(12):e173438). Of note, this alteration is also designated as 7235G>C in published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
GeneDx RCV000256059 SCV000321480 pathogenic not provided 2017-10-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7007G>C at the cDNA level. Located in the last nucleotide of exon 13, it disrupts a natural splice donor site and causes abnormal splicing. Multiple RNA analyses have demonstrated that BRCA2 c.7007G>C causes out-of-frame skipping of exons 12 and 13 (Serova-Sinilnikova 1997, Houdayer 2012). This variant, also defined as BRCA2 7235G>C using alternate nomenclature, has been reported in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Laitman 2011, Sagi 2011, Laitman 2012, Wang 2014). BRCA2 c.7007G>C was also reported in the compound heterozygous state with a frameshift variant in an individual with a phenotype consistent with Fanconi Anemia (Myers 2012). Although the nucleotide substitution results in the change of an Arginine to a Proline at codon 2336, and is called Arg2336Pro in the literature, we are only using the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. BRCA2 c.7007G>C was not observed at a significant frequency in large population cohorts (Lek 2016). The nucleotide which is altered, a Guanine (G) at base 7007, is conserved across species. Based on the current evidence, we consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077394 SCV000327566 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV000475905 SCV000541008 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045113 SCV000592087 pathogenic Hereditary breast and ovarian cancer syndrome 2013-01-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000214499 SCV000683838 pathogenic Hereditary cancer-predisposing syndrome 2020-05-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045113 SCV000695023 pathogenic Hereditary breast and ovarian cancer syndrome 2017-08-23 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7007G>C (p.Arg2336Pro) variant involves the alteration of a conserved nucleotide affecting the last nucleotide of the exon 13. 3/5 in silico tools predict damaging outcome for this variant. 4/5 splice prediction tools predict a significant impact on normal splicing. ESE finder predicts that this variant may generate a novel ESE site. Functional studies showed that the variant causes skipping of exons 12 and 13 (and increase of alternative splicing) (Serova-Sinilnikova, 1997, Houdayer, 2012). This variant is absent in 115936 control chromosomes from ExAC. The variant was found in multiple individuals with a personal/or family history of breast and/or ovarian cancer (Serova-Sinilnikova 1997, Sagi 2010, Adams 2011, Laitman 2011, Laitman 2012, Pritzlaff 2017, Wang 2014). In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
GeneKor MSA RCV000045113 SCV000821714 pathogenic Hereditary breast and ovarian cancer syndrome 2020-01-01 criteria provided, single submitter clinical testing This variation replaces Arginine with Proline at codon 2336 of the BRCA2 protein. The arginine residue is weakly conserved and is located in a domain of the protein that is not known to be functionally important. There is a moderate physicochemical difference between arginine and proline (Grantham Score 81). This variant also falls at the last nucleotide of exon 13 of the BRCA2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (rs28897743, ExAC no frequency). This variant has been reported in individuals with breast and/or ovarian cancer and Fanconi anemia (PMID: 9150172, PMID: 22399190, PMID: 21548014 ). This variant is also known as 7235G>C in the literature. Experimental studies have shown that this missense change causes skipping of exons 12 and 13 (PMID: 22505045). The mutation database ClinVar contains entries for this variant (Variation ID: 52241).
Daryl Scott Lab,Baylor College of Medicine RCV001269283 SCV001448627 pathogenic Fanconi anemia, complementation group D1 2020-11-11 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001310135 SCV001499683 pathogenic Breast-ovarian cancer, familial 1 2020-04-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000256059 SCV001502169 pathogenic not provided 2020-08-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077394 SCV000109191 pathogenic Breast-ovarian cancer, familial 2 2011-05-04 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077394 SCV000146992 pathogenic Breast-ovarian cancer, familial 2 2006-05-05 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045113 SCV000587879 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
King Laboratory,University of Washington RCV001171445 SCV001251356 pathogenic Breast-ovarian cancer, familial 2; Hereditary breast and ovarian cancer syndrome 2019-09-01 no assertion criteria provided research

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