ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3328_3330del (p.Lys1110del) (rs80358335)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000585901 SCV000076158 benign not provided 2019-03-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132199 SCV000187281 likely benign Hereditary cancer-predisposing syndrome 2018-01-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Intact protein function observed in appropriate functional assay(s),Insufficient evidence
GeneDx RCV000168501 SCV000321429 uncertain significance not specified 2016-12-21 criteria provided, single submitter clinical testing This in-frame deletion of 3 nucleotides in BRCA1 is denoted c.3328_3330delAAG at the cDNA level and p.Lys1110del (K1110del) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA1 3447_3449delAAG. The normal sequence, with the bases that are deleted in brackets, is TAAAA[delAAG]CAAG. This deletion of a single Lysine residue occurs at a position that is not conserved and is not located in a known functional domain. This variant has been observed in patients with personal and/or family history of breast and/or ovarian cancer (Ahmad 2012, Gleicher 2014, Mannan 2016). Functional studies by Bouwman et al. (2013) have suggested that BRCA1 Lys1110del is neutral based on insensitivity to cisplatin and ability to support growth similar to controls in BRCA1-deficient mouse embryonic stem cells. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider BRCA1 Lys1110del to be a variant of uncertain significance.
Counsyl RCV000112065 SCV000488064 uncertain significance Breast-ovarian cancer, familial 1 2015-12-22 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000168501 SCV000591437 uncertain significance not specified criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000585901 SCV000600326 benign not provided 2019-01-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000585901 SCV000699018 likely benign not provided 2016-03-28 criteria provided, single submitter clinical testing Variant summary: This variant affects non-conserved nucleotides and results in an in-frame deletion of a Lysine at codon 1110. Lys1110 is not highly conserved, as chicken, dog, cow, and opossum all have an alternate residue at this codon. Mutation Taster predicts a neutral outcome for the variant. It has been observed exclusively in the South Asian subcohort of the ExAc project at an allele frequency of 0.32% (54/16502; 1/306), which exceeds the maximal expected allele frequency of a disease causing BRCA1 allele (0.1%; 1/1000) by >3-fold, indicating a benign impact. The variant has been reported in HBOC spectrum patients without family history and co-segregation information, therefore it is uncertain if the variant was indeed responsible for the patients' disease. A functional study showed the variant to be able to complement the growth defect and cisplatin sensitivity of cells lacking endogenous BRCA1 expression, suggesting that the variant does not impair BRCA1 function (Bouwman_2013). Reputable clinical diagnostic laboratories classify variant as VUS (without evidence to further evaluate), while one has classified the variant as benign. Considering all evidences, the variant shows strong evidence for neutrality; it retains the reading frame, it is present at a high allele frequency in the South Asian subpopulation, and does not affect BRCA1 function in cell growth and DNA repair, therefore the variant was classified as likely benign.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000112065 SCV000744637 uncertain significance Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Color RCV000132199 SCV000902793 likely benign Hereditary cancer-predisposing syndrome 2015-06-01 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112065 SCV000144718 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112065 SCV000297599 likely benign Breast-ovarian cancer, familial 1 2008-11-11 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000112065 SCV000733629 uncertain significance Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing

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