ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3327_3329del (p.Lys1110del) (rs80357575)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129448 SCV000184218 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Insufficient evidence
GeneDx RCV000590069 SCV000210037 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing This deletion of 3 nucleotides is denoted BRCA1 c.3327_3329delAAA at the cDNA level and p.Lys1110del at the protein level. The normal sequence, with the bases that are deleted in brackets, is TAAA[delAAA]GCAA. Using alternate nomenclature, this variant is defined as 3446_3448delAAA or K1109del. This in frame deletion occurs in a region that is not conserved is not located in a known functional domain. In addition, a similar variant at the cDNA level, BRCA1 c.3328_3330delAAG, leads to the same deletion of a Lysine at position 1110, and this latter variant has been observed in multiple women with breast or ovarian cancer (Gleicher 2014, Ahmad 2012, Mannan 2016). In one functional study, BRCA1 c.3328_3330delAAG was considered to be neutral, causing similar activity as wild type in a cell proliferation and cisplatin sensitivity assay (Bouwman 2013). Despite this one normal assay, the clinical significance of this finding remains unclear at this time and we consider BRCA1 Lys1110del to be a variant of uncertain significance.
Invitae RCV000590069 SCV000259609 likely benign not provided 2018-08-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590069 SCV000699017 uncertain significance not provided 2017-04-27 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.3327_3329delAAA (p.Lys1110del) variant causes in frame deletion of one amino acid in a non-repetitive region in exon 10. One in silico tool predicts a benign outcome for this variant. This variant was found in 1/121194 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). Variant has been reported in affected individuals without strong evidence for causality. Functional study (Bouwman et al, 2013) showed a comparable level of expression level and functional activities as WT. The variant was able to restore the proliferation defect of switched embryonic stem cells similar to wild-type and it also allowed the proliferation in presence of ciplastin in similar manner to wild type. However, the authors did not indicate these assays to unanimously explain the pathogenicity of all variants found in BRCA1. Anczukow et al, 2008 tested the variant with minigene analysis and stated that this variant does not drastically affect splicing, although the extent of the effect was not shown. BIC reported variant in 2 indiviudals and one of them also carried a pathogenic variant in BRCA2 c.8755-1G>A, supporting a non-pathogenic role of variant of interest. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, without evidence for independent evaluation. Taken together, due to lack of solid functional studies or other evidences for clear classification, this variant is classified as VUS.
Counsyl RCV000112064 SCV000784882 uncertain significance Breast-ovarian cancer, familial 1 2017-01-17 criteria provided, single submitter clinical testing
Color RCV000129448 SCV000903064 likely benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112064 SCV000144717 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing
3DMed Clinical Laboratory Inc RCV000677819 SCV000803979 uncertain significance Cancer of the pancreas 2018-05-21 no assertion criteria provided clinical testing

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