ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3575T>G (p.Phe1192Cys) (rs80358606)

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Total submissions: 12
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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) RCV000077308 SCV001161580 benign Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00128 (Latino), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Invitae RCV001085848 SCV000072239 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130786 SCV000185679 likely benign Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing No disease association in appropriately sized case-control study(ies);Other data supporting benign classification
GeneDx RCV000755858 SCV000210593 likely benign not provided 2020-08-25 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22810696, 18284688, 28591715)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000755858 SCV000296713 likely benign not provided 2020-05-24 criteria provided, single submitter clinical testing
Counsyl RCV000077308 SCV000489626 uncertain significance Breast-ovarian cancer, familial 2 2016-11-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000254642 SCV000694706 likely benign not specified 2021-05-27 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3575T>G (p.Phe1192Cys) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251062 control chromosomes, predominantly at a frequency of 0.0013 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.73 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin.c.3575T>G has been reported in the literature in individuals affected with HBOC, colorectal cancer and gastroesophageal adenocarcinoma (Lee_2008; Keihimi_2017, Kato_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six labs classified the variant as likely benign/benign while two classified as VUS. Based on the evidence outlined above, the variant was classified as likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755858 SCV000883474 uncertain significance not provided 2017-07-10 criteria provided, single submitter clinical testing The BRCA2 c.3575T>G; p.Phe1192Cys variant (rs80358606) is reported in the ClinVar database as uncertain or likely benign (Variation ID: 51490), and observed in general population databases with an allele frequency of 0.13 percent (45/34404 alleles) in Latinos in the Genome Aggregation Database. The phenylalanine at codon 1192 is weakly conserved across species and computational algorithms (Align GVGD, SIFT, MutationTaster, Prior Probabilities) predict this variant to be tolerated. However, with the limited information regarding p.Phe1192Cys, its clinical significance is uncertain at this time. REFERENCES Link to ClinVar database for p.Phe1192Cys: https://www.ncbi.nlm.nih.gov/clinvar/variation/51490/
Color Health, Inc RCV000130786 SCV000903289 likely benign Hereditary cancer-predisposing syndrome 2017-04-26 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001646184 SCV001854770 likely 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) RCV000077308 SCV000109105 likely benign Breast-ovarian cancer, familial 2 2012-07-09 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077308 SCV000146261 uncertain significance Breast-ovarian cancer, familial 2 2001-10-29 no assertion criteria provided clinical testing

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