ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5634C>G (p.Asn1878Lys) (rs80358784)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 15
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031564 SCV001161520 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 = 0.000455
Invitae RCV001084469 SCV000072714 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-15 criteria provided, single submitter clinical testing
GeneDx RCV000168579 SCV000210615 likely benign not specified 2017-02-10 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000164012 SCV000214617 likely benign Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
Counsyl RCV000031564 SCV000488757 uncertain significance Breast-ovarian cancer, familial 2 2016-06-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000195372 SCV000600650 uncertain significance not provided 2020-07-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000164012 SCV000683718 likely benign Hereditary cancer-predisposing syndrome 2015-11-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000168579 SCV000916942 likely benign not specified 2020-07-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.5634C>G (p.Asn1878Lys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 248658 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.5634C>G, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and related tumor phenotypes (e.g. Borg 2010, Balia 2011, Lu 2012, Wong-Brown 2015, Dudley_2018). These reports however do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. Two functional studies from the same group utilizing homologous recombination assays to evaluate an impact on protein function, provided conflicting results about the variant (Spugnesi_2013, Balia_2011). However, a recent multifactorial likelihood analysis predicted this variant to be Benign (Parsons_2019). Nine other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (3x) or likely benign (5x), while the expert panel called the variant benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000031564 SCV001139118 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000195372 SCV001148987 uncertain significance not provided 2019-02-01 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642383 SCV001854845 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) RCV000031564 SCV000054169 likely benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031564 SCV000146648 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353709 SCV000591980 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Asn1878Lys variant was identified in 3 of 4892 proband chromosomes (frequency: 0.001) from individuals with case of breast cancer (Balia 2011, Capanu 2011). The variant was reported in dbSNP(ID: rs80358784) “With unknown allele”; however, the only frequency information available was from the “ClinSeq project” where the variant was found in one out of 662 participants (allele frequency: 0.001). The variant was identified eight times in UMD as an unclassified variant, and was also reported in the LOVD and HGMD databases. The p.Asn1878 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD) do not suggest a high likelihood of impact of the variant amino acid (Lys) to the protein. However, this information is not predictive enough to rule out pathogenicity. Loss of heterozygosity analysis of tumours from patients with the variant noted an absence of loss of heterozygosity in one study (Balia 2011); however, in another study the variant allele was lost, providing evidence for neutrality (Spearman 2008). Two assays evaluating homologous recombination activity of the variant yielded conflicting results. In a yeast-based assay, Spugnesi (2013) suggests that the variant may not be deleterious as it conferred a phenotype similar to wildtype. However, in a HeLa cell-based assay, the variant had a level of spontaneous homologous recombination similar to a known deleterious mutation, suggesting that the variant may be pathogenic (Balia 2011). Segregation and/or additional functional studies are recommended to further elucidate the pathogenicity of this variant. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735567 SCV000863705 uncertain significance Breast and/or ovarian cancer 2013-07-19 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.