ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2412G>C (p.Gln804His) (rs55746541)

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Total submissions: 11
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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) RCV000111853 SCV000244317 benign Breast-ovarian cancer, familial 1 2015-08-10 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 = 0.000446
Invitae RCV000590591 SCV000075843 benign not provided 2019-02-25 criteria provided, single submitter clinical testing
GeneDx RCV000120290 SCV000209938 likely benign not specified 2017-10-19 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 RCV000162976 SCV000213464 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing
Counsyl RCV000111853 SCV000220696 likely benign Breast-ovarian cancer, familial 1 2014-09-15 criteria provided, single submitter literature only
Color RCV000162976 SCV000683034 likely benign Hereditary cancer-predisposing syndrome 2015-07-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590591 SCV000698949 likely benign not provided 2016-08-24 criteria provided, single submitter clinical testing Variant summary: This c.2412G>C variant involves the alteration of a non-conserved nucleotide and results in a conservative substitution of Glutamine (Q) with Histidine (H). Both residues are medium size and polar; therefore this substitution unlikely to alter the physico-chemical properties of the protein. 3/4 in silico tools predict a neutral outcome. This variant is present at low frequency (0.006%; 7/121340 chromosomes) from ExAC not exceeding the maximal expected allele frequency of a disease causing BRCA1 allele. The variant has been recurrently reported in HBOC patients/families in several studies, however, there are 3 published (Konecny_2011, Tazzite_2012, Wadell_2008) and 3 unpublished (BIC, UMD, KConFab) reports that report the variants co-occurrence with another deleterious variant (4 of 6 reported to be present in BRCA2, the other 2 unspecified), an evidence that rules out pathogenicity. In addition, multifactorial likelihood-ratio model (e.g. Easton et al, Lindor et al) show a benign outcome for the variant. Several reputable databases and clinical labs have classified the variant as neutral, benign, or likely benign (ARUP, UMD, GeneDx, Ambry Genetics, KConFab). Taken together, the overall interpretation of this variant is Probably Normal variant until more information (co-segregation analysis, functional studies) becomes available.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000111853 SCV000744657 benign Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590591 SCV000888866 benign not provided 2016-02-20 criteria provided, single submitter clinical testing
ITMI RCV000120290 SCV000084442 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000111853 SCV000144422 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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