ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5059_5061GTT[1] (p.Val1688del) (rs80358344)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048753 SCV000076766 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-10 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 16 of the BRCA1 mRNA (c.5062_5064delGTT). This leads to the deletion of 1 amino acid residues in the BRCA1 protein (p.Val1688del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in multiple individuals and families affected with breast and/or ovarian cancer, with evidence of segregation with disease (PMID: 18165637, 19706752, 18821011, 8968102, 18703817, 23697973, 25814778, 26306726). ClinVar contains an entry for this variant (Variation ID: 55368). Experimental studies have shown that this in-frame deletion disrupts many aspects of the BRCA1 protein function, leading to defective DNA damage response and repair (PMID: 19706752, 23867111, 11157798). Based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000130452 SCV000185316 pathogenic Hereditary cancer-predisposing syndrome 2017-07-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Good segregation with disease (lod 1.5-3 = 5-9 meioses),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Other strong data supporting pathogenic classification,Structural Evidence
GeneDx RCV000235533 SCV000293207 pathogenic not provided 2017-08-18 criteria provided, single submitter clinical testing This in-frame deletion of three nucleotides in BRCA1 is denoted c.5062_5064delGTT at the cDNA level and p.Val1688del (V1688del) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 5181_5183delGTT or c.5062_5064del. The normal sequence, with the bases that are deleted in braces, is TGTT[GTT]ATGA. This deletion of a single Valine residue occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located within the BRCT1 domain (Narod 2004). BRCA1 Val1688del has been observed in familial breast and/or ovarian cancer cases (Montagna 1996, Malacrida 2008, Tazzite 2012) and was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious variants. Functional studies by Bouwman et al. (2013) have suggested that BRCA1 Val1688del is pathogenic based on its inability to rescue the proliferation defect in BRCA1 deficient mouse embryonic stem cells and a statistically significant increase in sensitivity to cisplatin compared to controls. Additional functional assessments have demonstrated that BRCA1 Val1688del disrupts interactions with known partner proteins (De Nicolo 2009) and causes deficient transactivation activity (Vallon-Christersson 2001). We consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112479 SCV000326126 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000112479 SCV000575701 pathogenic Breast-ovarian cancer, familial 1 2015-08-07 criteria provided, single submitter clinical testing
Color RCV000130452 SCV000683244 pathogenic Hereditary cancer-predisposing syndrome 2017-01-03 criteria provided, single submitter clinical testing
Mendelics RCV000048753 SCV000839220 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112479 SCV000145281 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496324 SCV000587449 uncertain significance not specified 2014-01-31 no assertion criteria provided research

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