ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5210_5212GAG[1] (p.Gly1738del) (rs80358347)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129556 SCV000184337 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000587393 SCV000699222 uncertain significance not provided 2016-07-28 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5213_5215delGAG variant leads to deletion of a highly conserved Glycine residue, located at the beginning of the flexible linker domain connecting the two BRCT (BRCA1 C-terminal) repeats. This domain has been reported to participate in the BRCT inter-repeat interface formation (Konstantopoulou_2004). Furthermore, 2 additional variants, namely, p.Gly1738Glu and p.Gly1738Arg have been classified as pathogenic in ClinVar, suggesting that Gly1738 is a critical amino acid for BRCA1 function. One in silico tool (Mutation Taster) predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SRp40 and SF2/ASF. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 121410 control chromosomes. It has been reported in at least four HBOC patients, to include, two patients from unrelated Slovakian families with HBOC (Konecny_2011) and two affected siblings of an unaffected carrier proband (@ an age less than the average age of onset of HBOC) identified at our laboratory (personal communication). In addition, multiple clinical diagnostic laboratories report this variant as "Pathogenic" (Myriad and ARUP), "VUS" (Ambry) or as "classification not provided" (InVitae) in the ClinVar database. Taken together, this variant is classified as "VUS-possibly pathogenic" until additional evidence confirming a functional impact of this variant and un-equivocal co-segregation with disease are identified.
PreventionGenetics,PreventionGenetics RCV000587393 SCV000806967 uncertain significance not provided 2017-10-27 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112567 SCV000145398 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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