ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4166G>A (p.Ser1389Asn) (rs78951648)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000417371 SCV000209969 likely benign not specified 2017-10-16 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.
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240719 SCV000265887 uncertain significance Breast neoplasm 2015-11-01 criteria provided, single submitter research
Ambry Genetics RCV000218513 SCV000273648 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-19 criteria provided, single submitter clinical testing The p.S1389N variant (also known as c.4166G>A), located in coding exon 10 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4166. The serine at codon 1389 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in multiple individuals of Asian descent affected with breast cancer (Haitian Z et al. Breast. 2008 Dec;17:563-7; Hansen TV et al. Fam. Cancer. 2011 Jun;10:207-12; Ahmad J et al. Clin. Genet. 2012 Dec;82:594-8; Zhong X et al. PLoS ONE. 2016 Jun;11:e0156789). This amino acid position is highly conserved through mammals, but not in all available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000417371 SCV000605867 uncertain significance not specified 2016-10-28 criteria provided, single submitter clinical testing
Counsyl RCV000077563 SCV000785858 uncertain significance Breast-ovarian cancer, familial 1 2017-12-29 criteria provided, single submitter clinical testing
Color Health, Inc RCV000218513 SCV000909276 likely benign Hereditary cancer-predisposing syndrome 2017-11-06 criteria provided, single submitter clinical testing
Mendelics RCV000077563 SCV001140533 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000417371 SCV001337978 uncertain significance not specified 2020-01-23 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4166G>A (p.Ser1389Asn) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251898 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4166G>A has been reported in the literature in individuals affected with breast cancer, ovarian cancer or colorectal cancer without strong evidence for causality (examples-Haitian_2008, Hansen_2011, Ahmad_2012, Akmal_2009, Zhong_2016, Li_2018, Toh_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (4x), likely benign (2x) and benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance
Invitae RCV001506260 SCV001711179 likely benign Hereditary breast and ovarian cancer syndrome 2020-10-25 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077563 SCV000109365 likely benign Breast-ovarian cancer, familial 1 2012-10-04 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077563 SCV000145002 uncertain significance Breast-ovarian cancer, familial 1 2009-08-07 no assertion criteria provided clinical testing

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