ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5573T>C (p.Ile1858Thr) (rs755427809)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166098 SCV000216865 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-11 criteria provided, single submitter clinical testing The p.I1858T variant (also known as c.5573T>C), located in coding exon 22 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5573. The isoleucine at codon 1858 is replaced by threonine, an amino acid with some similar properties. This alteration has been previously identified in two African American brothers with early onset prostate cancer (Zuhlke KA, Clin. Cancer Res. 2004 Sep; 10(18 Pt 1):5975-80).<span style="font-family:arial,sans-serif"> Based on protein sequence alignment, this amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae RCV000204222 SCV000262247 likely benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000239189 SCV000296476 uncertain significance not specified 2016-05-24 criteria provided, single submitter clinical testing
Counsyl RCV000662947 SCV000785908 uncertain significance Breast-ovarian cancer, familial 1 2018-01-08 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166098 SCV000908972 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-14 criteria provided, single submitter clinical testing
Mendelics RCV000662947 SCV001140462 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 RCV000239189 SCV001426973 uncertain significance not specified 2020-07-13 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5573T>C (p.Ile1858Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 249322 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (8e-05 vs 0.001), allowing no conclusion about variant significance. c.5573T>C has been reported in the literature in individuals affected with early-onset prostate cancer without strong evidence for causality (e.g. Zuhlke_2004). 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=2; uncertain significance, n=4). Based on the evidence outlined above, the variant was classified as uncertain significance.

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