ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8057T>C (p.Leu2686Pro) (rs28897746)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479056 SCV000565756 likely pathogenic not provided 2016-05-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8057T>C at the cDNA level, p.Leu2686Pro (L2686P) 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 8285T>C. This variant was observed in an individual diagnosed with Fanconi Anemia who also harbored a pathogenic variant in trans with BRCA2 Leu2686Pro (Dodgshun 2016). This variant was strongly predicted by Lindor et al. (2012) to be likely pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. BRCA2 Leu2686Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Leu2686Pro occurs at a position that is conserved across species and is located in the DNA binding domain, the nuclear export signal motif, and the SHFM1 binding domain (Marston 1999, Yang 2002, Jayesekharan 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider BRCA2 Leu2686Pro to be a likely pathogenic variant.
Ambry Genetics RCV000568548 SCV000666009 pathogenic Hereditary cancer-predisposing syndrome 2020-01-22 criteria provided, single submitter clinical testing The p.L2686P pathogenic mutation (also known as c.8057T>C), located in coding exon 17 of the BRCA2 gene, results from a T to C substitution at nucleotide position 8057. The leucine at codon 2686 is replaced by proline, an amino acid with similar properties. This variant was detected in trans with a pathogenic BRCA2 mutation in a patient diagnosed with Fanconi Anemia at 2 months of age, who later died of metastatic glioblastoma multiforme at age 4 (Dodgshun AJ. Cancer Genet. 2016;209:53-6). This alteration was defective in homology-directed DNA repair (HDR) assays, as well as a mouse ES cell growth assay (Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Mesman RLS et al. Genet. Med. 2019 02;21:293-302; Hart SN et al. Genet. Med. 2019 01;21:71-80). In addition, in a study utilizing a bioinformatics method that integrates information about protein sequence, conservation, and structure in a protein likelihood ratio, the effect of this alteration was predicted likely deleterious (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000479056 SCV000883517 likely pathogenic not provided 2017-12-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000568548 SCV001340336 likely pathogenic Hereditary cancer-predisposing syndrome 2019-10-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264563 SCV001442781 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-05 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8057T>C (p.Leu2686Pro) 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. The variant was absent in 251264 control chromosomes. c.8057T>C has been reported in the literature in one individual affected with Fanconi Anemia and a biallelic BRCA2 genotype (BRCA2 c.9672dupA (paternal) and c.8057T>C (maternal) (Dodgshun_2016). It was also identified in a proband from a family with Hereditary Breast And Ovarian Cancer (Azzollini_2016). At-least two multifactorial probability based assessments have classified this variant with a high probability of pathogenicity (example, Karchin_2008, Lindor_2012). Several publications report consistent experimental evidence evaluating an impact on protein function (example, Guidugli_2018, Hart_2019). The most pronounced variant effect results in defective homology directed repair. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic citing overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV001264563 SCV001478294 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-10 criteria provided, single submitter curation Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (19.2) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the VarCall Bayesian statistical model for VUS classification using functional assay data (Guidugli et al Am J Hum Genet 2018; 102:233-248, Couch Lab), the variant has a probability of being deleterious of 0.994 and an overall classification of pathogenic. (PS3_strong). There are two likely pathogenic classifications on ClinVar for this variant from accredited USA diagnostic laboratories (Ambry Genetics and GeneDx, 2016) (PP5_sup). Data not used in classification: There are additional reports of this variant in ClinVar (1), UMD (5), BIC (1), and BRCA2 LOVD (1).
Invitae RCV001264563 SCV001574246 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 2686 of the BRCA2 protein (p.Leu2686Pro). 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 observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Fanconi anemia (PMID: 26740091). This variant has also been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52489). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be deleterious (PMID: 19043619). However, this prediction has not been confirmed by published functional studies. In addition, based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data this variant has been determined to have a high probability of being pathogenic (PMID: 21990134). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113861 SCV000147259 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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