ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4985T>C (p.Phe1662Ser)

gnomAD frequency: 0.00001  dbSNP: rs28897695
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Total submissions: 9
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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) RCV000112441 SCV000244375 benign Breast-ovarian cancer, familial, susceptibility to, 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 = 0.000161
Ambry Genetics RCV000130003 SCV000184828 benign Hereditary cancer-predisposing syndrome 2016-03-01 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl RCV000112441 SCV000489327 benign Breast-ovarian cancer, familial, susceptibility to, 1 2016-09-21 criteria provided, single submitter clinical testing
GeneDx RCV001703954 SCV000526839 likely benign not provided 2019-03-14 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17924331, 18951461, 26778126, 25724305, 22753008, 21990134, 20516115, 17305420, 25777348, 17262179, 21447777, 27124784, 27272900, 28364669, 30209399, 30415210, 28111427, 30765603, 33087888)
Color Health, Inc RCV000130003 SCV000911091 benign Hereditary cancer-predisposing syndrome 2016-02-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000443012 SCV000916779 benign not specified 2019-10-11 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4985T>C (p.Phe1662Ser) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant affects the second to last nucleotide of exon 15, however 4/5 computational tools predict no significant impact on normal splicing which has been confirmed by a validated mini-gene assay (Ahlborn_2015). The variant allele was found at a frequency of 0.00011 in 272494 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.00011 vs 0.001), allowing no conclusion about variant significance. The variant, c.4985T>C, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (ElSaghir_2015, Park_2017, Ryu_2017, Judkins_2005), without strong evidence for causality. In addition, the variant is reported in a large Japanese case-control study at a higher frequency in controls compared to cases (Momozawa_2018), further evidence for the benign nature of this variant. A co-occurrence with another pathogenic BRCA1 variant, c.5074+1G>A, providing supporting evidence for a benign role. The variant has been reported as benign by several computational methods, including likelihood ratios models which include functional assays (Woods_2016, Millot_2012, Thouvenot_2016). A functional study reporting a transcriptional activation assay classified the variant as non-pathogenic based on this assay (Fernandes_2019). Five ClinVar submissions (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV001421999 SCV001624533 likely benign Hereditary breast ovarian cancer syndrome 2021-11-19 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112441 SCV000145231 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-02-20 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112441 SCV001238382 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro

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