ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5059GTT[1] (p.Val1688del) (rs80358344)

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Total submissions: 13
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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) RCV000112479 SCV001161552 pathogenic Breast-ovarian cancer, familial 1 2019-06-18 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 5 based on posterior probability = 0.998076
Invitae RCV000048753 SCV000076766 pathogenic Hereditary breast and ovarian cancer syndrome 2020-08-27 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 The c.5062_5064delGTT pathogenic mutation (also known as p.V1688del) is located in coding exon 15 of the BRCA1 gene. This pathogenic mutation results from an in-frame GTT deletion at nucleotide positions 5062 to 5064. This results in the in-frame deletion of a valine at codon 1688. This alteration has been classified as pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Lindor, NM et al. Hum Mutat. 2012 Jan;33(1):8-21; Easton DF et al. Am. J. Hum. Genet., 2007 Nov;81:873-83). This alteration has been identified in multiple breast and ovarian cancer families and has been described as an Italian founder mutation (Montagna, M et al. Cancer Res. 1996 Dec 1;56(23):5466-9; De Nicolo, A et al. Cancer Res. 2009 Sep 1;69(17):7030-7; Tazzite A et al. Gynecol. Oncol., 2012 Jun;125:687-92; Minucci A et al. Expert Rev. Mol. Diagn., 2015 Aug;15:1383-403; Maxwell KN et al. Am. J. Hum. Genet., 2016 May;98:801-17). In one family this alteration segregated with disease in six of six affected sisters and was absent in two healthy relatives (Malacrida, S et al. J Clin Oncol. 2008 Jan 1;26(1):26-31). In addition, functional analyses have shown that this alteration leads to a protein that partially disrupts the BRCA1 BRCT domain, compromises protein stability, displays deficient DNA damage response function, and fails to associate with known partner proteins (De Nicolo, A et al. Cancer Res. 2009 Sep 1;69(17):7030-7). Furthermore, a yeast-based transcriptional assay showed that this alteration displayed no transcriptional activity compared to wildtype (Vallon-Christersson, J et al. Hum Mol Genet. 2001 Feb 15;10(4):353-60). This alteration has also been classified as likely to be deleterious based on a interspecific sequence variation classification system (Abkevich V et al. J. Med. Genet., 2004 Jul;41:492-507). A computational study reported this alteration as pathogenic based on data derived from an in vitro functional assay (Iversen ES et al. Cancer Epidemiol. Biomarkers Prev., 2011 Jun;20:1078-88). Of note, this alteration is also designated as 5181del3 in published literature. Based on the available evidence, c.5062_5064delGTT is classified as a pathogenic mutation.
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 Health, Inc 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
Mendelics RCV000112479 SCV001140494 pathogenic Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048753 SCV001360567 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-24 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5062_5064delGTT (p.Val1688del) results in an in-frame deletion that is predicted to remove one conserved hydrophobic residue (Valine) from the encoded protein and located in beta3 in the BRCT-N domain (Vallon-Christersson_2001). The variant was absent in 251360 control chromosomes (gnomAD). c.5062_5064delGTT has been reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Vallon-Christersson_2001, Malacrida_2008, De Nicolo_2009). In addition, this variant was co-segregated with disease in multiple families (Malacrida_2008, De Nicolo_2009). These data indicate that the variant is very likely to be associated with disease. Functional studies reports this variant affects protein stability, DNA damage response, association with BRCA1 partner proteins and transcriptional activity (Vallon-Christersson_2001, De Nicolo_2009). Seven ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000112479 SCV001553218 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The BRCA1 p.Val1688del is an in-frame deletion variant and was identified in 9 of 122 proband chromosomes (frequency: 0.074) from individuals or families of Italian descent with breast and ovarian cancer (Ramunas-Janavicius 2010). The variant was also identified in dbSNP (ID: rs80358344) a “With Pathogenic allele”; ClinVar and Clinvitae databases (Pathogenic by Ambry Genetics, GeneDx and Uncertain significance by Breast Cancer Information Core (BIC)); ARUP Laboratories BRCA Mutations Database (1X Definitely pathogenic); COGR database (unknown significance by MESHWCRI and likely pathogenic by CVH); BIC database (6X with unknown clinical importance); The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict altered splicing; this is not very predictive of pathogenicity. Several functional and co-segregation studies provide evidence that the p.Val1688del is deleterious. Using multi modal analysis approach, comprising comparative structural modeling, analysis of protein stability and associations, and analysis of DNA repair function, predicted BRCT domain destabilization and folding disruption caused by BRCA1 p.V1688del. Consistently, the recombinant delta ValBRCA1 was less stable than wtBRCA1 and, unlike the latter, failed to associate with BRIP1, CtIP, and Rap80, and to re-localize to sites of DNA damage. Yeast two-hybrid analysis revealed a compromised interaction with FHL2 and with KPNA2, which is likely responsible for improper subcellular localization of delta ValBRCA1. They concluded the variant is deleterious impairing protein stability and function (DeNicolo 2009). An analysis, integrating five independent evidences of disease causality including segregation, tumor pathology, and evolutionary and epidemiologic data, a final score of 349,000:1 in favor of disease causality was obtained. In one family the variant co-segregated with 6/6 breast cancer affected sisters and was not found in 2 healthy sisters who had not inherited the variant. In another family all affected members carried the mutation including a maternal aunt with cervical cancer (Malacrida 2008). Several lines of evidence have suggested that BRCA1 as a transcription regulator and it has been demonstrated that disease-associated mutations abolish the transactivation by BRCA1 in different experimental systems. The V1688del variant displayed loss of activity suggesting that it represents a cancer-associated mutation (Vallon-Christersson 2001). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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