ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7529T>C (p.Leu2510Pro) (rs80358979)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478444 SCV000567107 likely pathogenic not provided 2017-11-01 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7529T>C at the cDNA level, p.Leu2510Pro (L2510P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). BRCA2 Leu2510Pro, previously published as BRCA2 7757T>C using alternate nomenclature, has been identified in trans with a pathogenic BRCA2 variant in two siblings with Fanconi Anemia (Hirsch 2004, Alter 2007). Additionally, this variant has been shown to be hypersensitive to DNA-damaging agents, lead to increased chromosomal aberrations, and to be deficient in a cell-based homology-directed DNA break repair assay (Biswas 2011, Guidugli 2013). However, Biswas et al. (2011) also showed that this variant was able to rescue embryonic stem cell lethality although the rescued cells had reduced viability suggesting that this is hypomorphic allele. BRCA2 Leu2510Pro 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 Leu2510Pro occurs at a position that is conserved across species and is located within the DNA binding domain, the DSS1 contacting residue, and the FANCD2 binding domain (Yang 2002, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on the currently available evidence, we consider BRCA2 Leu2510Pro to be a likely pathogenic variant. While the cancer risks associated with this variant have not been established, this variant has been suggested to confer lower cancer risks than those of typical BRCA2 pathogenic variants (Biswas 2011); the risks presented here might be overestimates for the current patient. A clearly pathogenic BRCA2 variant would be indicative of Hereditary Breast and Ovarian Cancer (HBOC) syndrome, an autosomal dominant condition that predisposes to breast and ovarian cancer as well as other cancers. Lifetime risks are estimated to be 41% to 84% for female breast cancer and 11% to 27% for ovarian (Ford 1998, Antoniou 2003, Risch 2006). Graeser et al. (2009) found that women who harbor a BRCA2 pathogenic variant have an increased risk for contralateral breast cancer that is dependent on age at initial diagnosis. It is estimated that the risk to develop a second breast cancer within 10 years of the first diagnosis if initially diagnosed less than age 40 is 21%, between ages 40 and 50 is 13% and after age 50 is 9%. Additionally, it is estimated that the risk to develop a second breast cancer within 25 years of the first diagnosis if initially diagnosed less than age 40 is 63%, between ages 40 and 50 is 49% and after age 50 is 17%. BRCA2 pathogenic variants have also been reported in women with fallopian tube, primary peritoneal, and serous uterine cancer (Levine 2003, Biron-Shental 2006). Other cancer risks associated with a BRCA2 pathogenic variant include up to a 7% risk for pancreatic cancer (Ozcelik 1997, The Breast Cancer Linkage Consortium 1999), up to a 34% risk for prostate cancer in male carriers (Thompson 2001) and up to a 7% risk for male breast cancer (Liede 2004, Tai 2007). BRCA2 pathogenic variants have also been associated with an increased risk for cutaneous malignant melanoma (The Breast Cancer Linkage Consortium 1999, Liede 2004). The National Comprehensive Cancer Network has management guidelines for individuals with pathogenic variants in BRCA2 (NCCN). Fanconi Anemia (FA) is a rare autosomal recessive condition that can be caused by two pathogenic variants (one affecting each allele) in the BRCA2 gene. This condition is characterized by an increased risk for malignancy in children, including leukemia and certain solid tumors, as well as physical abnormalities (short stature, thumb and/or forearm malformations) and bone marrow failure. If both parents carry a BRCA2 pathogenic variant, the risk to have a child with FA is 25% for each pregnancy.
Ambry Genetics RCV000509658 SCV000607817 pathogenic Hereditary cancer-predisposing syndrome 2020-02-12 criteria provided, single submitter clinical testing The p.L2510P pathogenic mutation (also known as c.7529T>C), located in coding exon 14 of the BRCA2 gene, results from a T to C substitution at nucleotide position 7529. The leucine at codon 2510 is replaced by proline, an amino acid with similar properties. This alteration has been detected in two siblings with Fanconi anemia (FA) in trans with a BRCA2 pathogenic mutation (Hirsch B et al. Blood. 2004 Apr;103:2554-9; Alter BP et al. J. Med. Genet. 2007 Jan;44:1-9). Using a mouse embryonic stem cell-based functional assay and homologous recombination-mediated DNA repair (HDR) assays, this alteration has been shown to have hypersensitivity to different DNA-damaging agents, deficiency in RAD51 foci formation and homologous recombination efficiency, increased chromosomal aberrations, and reduced binding to an essential cofactor, DSS1 (Biswas K et al. Blood. 2011 Sep;118:2430-42; 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, 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.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV001290186 SCV001478276 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-09 criteria provided, single submitter curation Data used in classification: The frequency of this variant is 0/138,632 individuals in gnomAD (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (25.1) (PP3-sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). This variant has been reported in trans with another BRCA2 variant to cause Fanconi Anaemia (Hirsch et al Blood 2004; 103:2554-2559) (PM3_mod). This variant is classified on ClinVar as likely pathogenic by 2 accredited USA diagnostic laboratories (Ambry Genetics and GeneDx) (PP5_sup). Data not used in classification: There are additional reports of this variant in BIC (2), and BRCA2 LOVD (2).
OMIM RCV000009936 SCV000030157 pathogenic Fanconi anemia, complementation group D1 2004-04-01 no assertion criteria provided literature only
Breast Cancer Information Core (BIC) (BRCA2) RCV000113772 SCV000147114 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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