ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3327_3329del (p.Lys1110del) (rs80357575)

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Total submissions: 10
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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 2018-11-21 criteria provided, single submitter clinical testing ​The c.3327_3329delAAA variant (also known as p.K1110del), located in coding exon 9 of the BRCA1 gene, results from a deletion of three nucleotides between positions 3327 and 3329, causing the in-frame deletion of a lysine residue at codon 1110. This alteration has been reported as a variant of uncertain clinical significance in a cohort of patients who underwent clinical BRCA1 screening by whole gene direct DNA sequencing (Judkins T et al. Cancer Res. 2005 Nov;65:10096-103). A similar alteration resulting in the same in-frame deletion of a lysine residue at codon 1109 (c.3328_3330delAAG) has been reported in an individual with breast cancer, however, it has also been predicted neutral based on a functional complementation assay (Ahmad J et al. Clin. Genet. 2012 Dec;82:594-8; Bouwman P et al. Cancer Discov. 2013 Oct;3:1142-55). The deleted amino acid position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
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 RCV001089174 SCV000259609 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 Health, Inc RCV000129448 SCV000903064 likely benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
ACT Genomics, RCV001169843 SCV001250608 uncertain significance Breast neoplasm 2020-04-27 criteria provided, single submitter clinical testing This variant c.3327_3329delAAA (p.Lys1110del) results in a in-frame deletion of a lysine at position 1110 of the BRCA1 gene. The allele frequency of this variant is 0.000054 in East Asian of gnomAD Exomes. For the insufficient evidences, this variant has been classified as variant of uncertain significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285904 SCV001472409 uncertain significance none provided 2019-11-03 criteria provided, single submitter clinical testing The BRCA1 c.3327_3329delAAA; p.Lys1110del variant (rs80357575) has been published in the literature in individuals with breast cancer (Ahmad 2012, Mehta 2018, Shah 2018). The variant is reported in the ClinVar database (Variation ID: 125625) and in the general population with an overall allele frequency of 0.001% (3/250,252 alleles) in the Genome Aggregation Database. The lysine at this position is moderately conserved and does not occur in a known functional domain. Additionally, at least one functional study shows this variant behaves like wild type (Bouwman 2013). Due to limited information, the clinical significance of the p.Lys1110del variant is uncertain at this time. References: Ahmad J et al. Detection of BRCA1/2 mutations in breast cancer patients from Thailand and Pakistan. Clin Genet. 2012 Dec;82(6):594-8. Bouwman P et al. A high-throughput functional complementation assay for classification of BRCA1 missense variants. Cancer Discov. 2013 Oct;3(10):1142-55. Mehta A et al. Germline BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance associated with breast/ovarian cancer: a report from North India. Cancer Manag Res. 2018 Nov 30;10:6505-6516. Shah ND et al. Mutation analysis of BRCA1/2 mutations with special reference to polymorphic SNPs in Indian breast cancer patients. Appl Clin Genet. 2018 May 9;11:59-67.
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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