ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.212G>C (p.Arg71Thr) (rs80356913)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000584047 SCV000688368 pathogenic Hereditary cancer-predisposing syndrome 2017-08-07 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258471 SCV000325250 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785200 SCV000923768 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Invitae RCV000537219 SCV000635832 likely pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-26 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 71 of the BRCA1 protein (p.Arg71Thr). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and threonine. It also falls at the last nucleotide of exon 4 of the BRCA1 coding sequence. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 267512). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). While there is no experimental evidence for this variant, two different substitutions at this codon (c.211A>G and c.212G>A) have been determined to be pathogenic. Experimental evidence using RT-PCR and mini-gene assays has shown that these substitutions destroy the exon 4 natural splice donor site, leading to the usage of a cryptic site located 22 nucleotides upstream (PMID: 11385711, 21863257, 23451180, 22505045, 20215541). As a result a premature stop codon is generated. In summary, this is a rare variant in a consensus splice site where other variants have been determined to be pathogenic. This indicates that nucleotide changes at this site disrupt splicing, leading to the loss of BRCA1 protein expression and/or function. In the absence of segregation and/or functional evidence for this specific change, it has been classified as Likely Pathogenic.

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