ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7958T>C (p.Leu2653Pro) (rs80359022)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000505706 SCV000210452 pathogenic not provided 2017-10-19 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.7958T>C at the cDNA level, p.Leu2653Pro (L2653P) at the protein level, and results in the change of a Leucine to a Proline (CTT>CCT). Using alternate nomenclature, this variant would be defined as BRCA2 8186T>C. Functional studies have determined that BRCA2 Leu2653Pro produces a defective protein with respect to homology-directed DNA repair, ability to rescue lethality in BRCA2-deficient mouse embryonic stem cells, sensitivity to DNA-damaging agents, and genomic integrity (Biswas 2012, Guidugli 2013). Furthermore, this variant was strongly predicted by Lindor et al. (2012) to be deleterious based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants. BRCA2 Leu2653Pro was not observed in large population cohorts (Lek 2016). Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Leu2653Pro occurs at a position that is conserved across species and is located in the DNA binding domain and the DSS1 contacting residue (Yang 2002). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. 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 RCV000113844 SCV000327771 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000575206 SCV000665947 likely pathogenic Hereditary cancer-predisposing syndrome 2019-01-07 criteria provided, single submitter clinical testing The p.L2653P variant (also known as c.7958T>C), located in coding exon 16 of the BRCA2 gene, results from a T to C substitution at nucleotide position 7958. The leucine at codon 2653 is replaced by proline, an amino acid with similar properties. This alteration has been detected in high-risk breast/ovarian cancer families including one woman whose ovarian tumor demonstrated somatic loss of BRCA2 heterozygosity (Farrugia DJ et al. Cancer Res. 2008 May;68:3523-31; Bernards SS et al. Gynecol. Oncol. 2016 Feb;140:221-5). The p.L2653P variant is located in the DNA binding domain of BRCA2 and has been shown in multiple studies to significantly decrease DNA damage repair activity (Farrugia DJ et al. Cancer Res. 2008 May;68:3523-31; Biswas K et al. Hum. Mol. Genet. 2012 Sep;21:3993-4006; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 02;102:233-248; Hart SN et al. Genet. Med. 2019 01;21:71-80; Mesman RLS et al. Genet. Med., 2019 02;21:293-302). This alteration has been classified as definitely pathogenic 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 DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Color Health, Inc RCV000575206 SCV000683922 pathogenic Hereditary cancer-predisposing syndrome 2017-03-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505706 SCV000889143 pathogenic not provided 2019-01-03 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data are high quality (0/282708 chr). Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Moderate co-segregation with disease, and data include affected and unaffected individuals from multiple families.
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000770732 SCV000902213 likely pathogenic Breast and/or ovarian cancer 2017-08-28 criteria provided, single submitter clinical testing
Invitae RCV001381193 SCV001579493 pathogenic Hereditary breast and ovarian cancer syndrome 2020-07-24 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 2653 of the BRCA2 protein (p.Leu2653Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with hereditary breast and ovarian cancer in several families (PMID: 22678057) and in an unrelated individual affected with ovarian cancer (PMID: 29061967). ClinVar contains an entry for this variant (Variation ID: 52447). Experimental studies have shown that this missense change leads to a DNA repair defect, increased genomic instability and a 60-70% reduced rescue of BRCA2 null cell lines (PMID: 22678057). In addition, multifactorial algorithms developed specifically for the BRCA2 gene (PMID: 23108138, 19043619, 17924331, 21990134), suggest that this missense change is likely to be deleterious. For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113844 SCV000147227 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113844 SCV000297558 likely pathogenic Breast-ovarian cancer, familial 2 2012-08-15 no assertion criteria provided clinical testing

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