ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9875C>T (p.Pro3292Leu) (rs56121817)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077478 SCV001161630 benign Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000108
Invitae RCV000195340 SCV000073921 benign Hereditary breast and ovarian cancer syndrome 2020-12-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131346 SCV000186321 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-14 criteria provided, single submitter clinical testing The p.P3292L variant (also known as c.9875C>T), located in coding exon 26 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9875. The proline at codon 3292 is replaced by leucine, an amino acid with similar properties. This alteration has been reported in multiple breast and ovarian cancer patients (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40; Capanu M et al. Genet. Epidemiol. 2011 Jul;35:389-97; Gabaldó Barrios X et al. Fam. Cancer. 2017 Oct;16:477-489; Chao A et al. Oncotarget. 2016 Dec;7:85529-85541; Francies FZ et al. BMC Cancer. 2015 Nov;15:912; Elimam AA et al. BMC Med. Genet. 2017 08;18:85; Diaz-Zabala HJ et al Cancers (Basel). 2018 Nov;10). This alteration has also been reported in a patient with pancreatic ductal adenocarcinoma (Takeuchi S et al. Sci Rep. 2018 May;8:8105). In silico modeling predicts a possible impact of p.P3292L on the BRCA2-RAD51 interaction and phosphorylation-mediated activities; however, supporting experimental evidence is not available (Tram E et al. PLoS One. 2013 May;8:e62468). In one study, experiments based on the Avian counterpart of P3292L variant suggested that this alteration disrupts the BRCA2 protein's ability to bind to RAD51 and disrupts the cells' ability to undergo normal cell cycle without affecting the homologous recombination repair function of the protein (Ayoub N et al. Curr. Biol. 2009 Jul;19:1075–85). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000513762 SCV000210519 likely benign not provided 2020-09-08 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 32444794, 31409081, 31509718, 30199306, 30287823, 30400234, 29802286, 31131967, 29126202, 28814288, 28477318, 27907908, 27211102, 26566862, 26577449, 24372583, 25589618, 26740942, 19540122, 24323938, 18593900, 15800615, 20104584, 23704879)
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000513762 SCV000228418 uncertain significance not provided 2014-12-23 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000077478 SCV000267833 likely benign Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000513762 SCV000296514 likely benign not provided 2020-08-24 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000077478 SCV000383806 likely benign Breast-ovarian cancer, familial 2 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000301085 SCV000383807 likely benign Fanconi anemia, complementation group D1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000045908 SCV000538504 uncertain significance not specified 2016-10-20 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 Br.Ca. patient, functional study shows potential impact (not enough to go above VUS); ClinVar: 4 VUS, 2 LB
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000513762 SCV000610403 uncertain significance not provided 2017-03-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045908 SCV000695277 benign not specified 2019-01-18 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9875C>T (p.Pro3292Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.9e-05 in 247930 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (8.9e-05 vs 0.00075) however, the variant could still represent a rare polymorphism. c.9875C>T has been reported in the literature in individuals affected with breast and/or ovarian cancer, sarcoma, metastatic castration-resistant prostate cancer and pancreatic ductal adenocarcinoma (Abulkhair_2018, Diaz-Zabala_2018, Takeuchi_2018, Annala_2017, Barrios_2017, Ballinger_2016, Chao_2016, Francies_2015, Riahi_2015, Borg_2010). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.3922G>T, p.Glu1308X; BRCA2 c.9117G > A, p.Pro3039Pro; BRCA2 9502delT, c.9274delT, p.Tyr3092Ilefs)(Barrios_2017, ClinVar, BIC database), providing supporting evidence for a benign role. Furthermore, in a Fanconi anemia patient carrying this variant, variants were detected in FANCC gene (c.37C>T, p.Gln13X; c.1069C>T, p.Gln357X) (Nicchia_2015), providing supporting evidence for a benign role in this specific case. Experimental evidence evaluating an impact on protein function reported the variant as not being disruptive to the interaction of BRCA2 with RAD51, RAD51 foci formation was not significantly impaired following DNA damage induction and no significant increase in sensitivity to mitomycin C and etoposide was observed (Esashi _2005, Hucl _2008). Nine ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance (5x), likely benign (3x) and once as benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000195340 SCV000838912 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000513762 SCV000885091 uncertain significance not provided 2017-11-14 criteria provided, single submitter clinical testing The BRCA2 c.9875C>T; p.Pro3292Leu variant is described in the medical literature in individuals and families with breast cancer (Borg 2010, Francies 2015, Riahi 2015, Chao2016). However, the variant was also published in an individual with Fanconi anemia who also carried two nonsense variants in the FANCC gene (Nicchia 2015). The variant is listed in the ClinVar database as both a variant of uncertain significance and as likely benign/benign (Variation ID: 52910). The variant is listed in the dbSNP variant database (rs56121817) and in the Genome Aggregation Database in 20/245936 alleles. The proline at this position is conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. While in silico studies imply this variant may impact function (Tram 2013) functional studies show that this variant has no effect on at least some functions (Eashi 2005, Hucl 2008). Considering available information, this variant cannot be classified with certainty. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Chao A et al. Prevalence and clinical significance of BRCA1/2 germline and somatic mutations in Taiwanese patients with ovarian cancer. Oncotarget. 2016 Dec 20;7(51):85529-85541. Esashi F et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature. 2005 Mar 31;434(7033):598-604. Francies FZ et al. BRCA1, BRCA2 and PALB2 mutations and CHEK2 c.1100delC in different South African ethnic groups diagnosed with premenopausal and/or triple negative breast cancer. BMC Cancer. 2015 Nov 17;15:912. Hucl T et al. A syngeneic variance library for functional annotation of human variation: application to BRCA2. Cancer Res. 2008 Jul 1;68(13):5023-30. Nicchia E et al. Identification of point mutations and large intragenic deletions in Fanconi anemia using next-generation sequencing technology. Mol Genet Genomic Med. 2015 Jul 2;3(6):500-12. Riahi A et al. Mutation spectrum and prevalence of BRCA1 and BRCA2 genes in patients with familial and early-onset breast/ovarian cancer from Tunisia. Clin Genet. 2015 Feb;87(2):155-60. Tram E et al. Missense variants of uncertain significance (VUS) altering the phosphorylation patterns of BRCA1 and BRCA2. PLoS One. 2013 May 21;8(5):e62468.
Color Health, Inc RCV000131346 SCV000902771 benign Hereditary cancer-predisposing syndrome 2016-05-30 criteria provided, single submitter clinical testing
Mendelics RCV000077478 SCV001139277 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646971 SCV001852864 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000077478 SCV000109276 likely benign Breast-ovarian cancer, familial 2 2008-06-05 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077478 SCV000145724 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357526 SCV001553023 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Pro3292Leu variant was identified in 6 of 7398 proband chromosomes (frequency: 0.0008) from individuals or families with breast, ovarian or pancreatic cancer and was not identified in 874 control chromosomes from healthy individuals (Borg 2010, Capanu 2011, Francies 2015, Riahi 2015, Takeuchi 2018). The variant was also identified in dbSNP (ID: rs56121817) as "With other allele", ClinVar (classified as benign by Invitae; as likely benign by GeneDx, SCRP and three other submitters; as uncertain significance by six submitters), LOVD 3.0 (8x), and in UMD-LSDB (14X as unclassified variant). The variant was identified in control databases in 20 of 245936 chromosomes at a frequency of 0.00008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 5478 chromosomes (freq: 0.0004), Latino in 2 of 33562 chromosomes (freq: 0.00006), European in 6 of 111458 chromosomes (freq: 0.00005), Ashkenazi Jewish in 1 of 9844 chromosomes (freq: 0.0001), East Asian in 9 of 17246 chromosomes (freq: 0.0005), while the variant was not observed in the African, Finnish, and South Asian populations. In function studies Huci et al found that the p.Pro3292Leu variant was not sensitive to mitomycin C and etoposide induced DNA damage compared to wildtype unlike a truncating variant that was studied, moreover BRCA2/RAD51 foci formed normally with the variant present suggesting that the variant does not have clinical significance (Huci 2008). However, based on the location of the variant it is predicted to disrupt the sequence motif of the CDK2 kinase and affects interaction with RAD51 (Krassowski 2018, Tram 2013). Although the p.Pro3292 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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