ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7534C>T (p.Leu2512Phe) (rs80358980)

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Total submissions: 14
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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) RCV000113773 SCV001161533 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 = 0.000428
Invitae RCV001085013 SCV000073252 benign Hereditary breast and ovarian cancer syndrome 2020-11-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130690 SCV000185577 likely benign Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene;Structural Evidence
GeneDx RCV001705702 SCV000210428 likely benign not provided 2021-03-09 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 24489791, 31131967, 19043619, 21120943, 27914478, 12228710, 25964535, 10923033, 18951461, 28283652, 30254663, 28288110, 30588330, 30199306, 32994724, 33067490)
Counsyl RCV000113773 SCV000220890 likely benign Breast-ovarian cancer, familial 2 2014-11-14 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212260 SCV000600754 uncertain significance not specified 2017-04-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130690 SCV000683885 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212260 SCV000695076 uncertain significance not specified 2019-12-20 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7534C>T (p.Leu2512Phe) results in a non-conservative amino acid change located in the helical domain (IPR015252) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 348928 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7534C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence of causality (e.g. Zuntini_2018, Shimelis_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant(s) have been reported (BRCA1 c.4760C>G, p.Ser1587X), providing supporting evidence for a benign role (UMD database). In addition, several computational and multifactorial models suggest this variant as neutral or likely benign (Whiley_2014, Karchin_2008). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other ClinVar submitters cite the variant as benign/likely benign (n=2) or uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Research and Development, ARUP Laboratories RCV001646664 SCV001854933 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
Breast Cancer Information Core (BIC) (BRCA2) RCV000113773 SCV000147115 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113773 SCV000297553 uncertain significance Breast-ovarian cancer, familial 2 2006-10-17 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356168 SCV001551258 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Leu2512Phe variant was identified in 3 of 100,182 proband chromosomes (frequency: 0.00003) from individuals or families with breast or ovarian cancer (Caux-Moncoutier 2011, Maistro 2016, Shimelis 2017) and in 1 of 97,576 control chromosomes (frequency: 0.00001) from healthy individuals (Shimelis 2017). The variant was also identified in dbSNP (ID: rs80358980) as "With other allele", ClinVar (classified as benign by Invitae; as likely benign by GeneDx and Counsyl; and as uncertain significance by Ambry Genetics and five other submitters), LOVD 3.0 (4x), UMD-LSDB (8x as unclassified variant), BIC Database (4x as unknown significance), and ARUP Laboratories (Likely not pathogenic or of little clinical significance) databases. The variant was identified in control databases in 6 of 246118 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5484 chromosomes (freq: 0.0002), Latino in 3 of 33576 chromosomes (freq: 0.00009), European Non-Finnish in 1 of 111612 chromosomes (freq: 0.000009), and South Asian in 1 of 30770 chromosomes (freq: 0.00003), while it was not observed in the African, Ashkenazi Jewish, East Asian, or European Finnish populations. One clinical laboratory reports identifying this variant as homozygous variant in an individual with no personal or family history of Fanconi anemia. The p.Leu2512 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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. This variant is classified as a variant of uncertain significance.
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV001705702 SCV001932515 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000212260 SCV001953576 benign not specified no assertion criteria provided clinical testing

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