ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3328_3330del (p.Lys1110del) (rs80358335)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001079725 SCV000076158 benign Hereditary breast and ovarian cancer syndrome 2020-12-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132199 SCV000187281 likely benign Hereditary cancer-predisposing syndrome 2019-03-30 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Intact protein function observed in appropriate functional assay(s);Subpopulation frequency in support of benign classification
GeneDx RCV000585901 SCV000321429 likely benign not provided 2021-05-10 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 10923033, 30555256, 29785135, 19370767, 26911350, 23867111, 25036526, 22486713, 16267036)
Counsyl RCV000112065 SCV000488064 uncertain significance Breast-ovarian cancer, familial 1 2015-12-22 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000112065 SCV000744637 uncertain significance Breast-ovarian cancer, familial 1 2015-09-21 criteria provided, single submitter clinical testing
Color Health, Inc RCV000132199 SCV000902793 likely benign Hereditary cancer-predisposing syndrome 2015-06-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170595 SCV001333184 likely benign Breast and/or ovarian cancer 2018-07-24 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001284870 SCV001470964 uncertain significance none provided 2019-11-05 criteria provided, single submitter clinical testing The BRCA1 c.3328_3330delAAG; p.Lys1110del variant (rs80358335) is reported in the literature in individuals with breast and/or ovarian cancer (Ahmad 2012, Mannan 2016, Mehta 2018), and is reported in ClinVar (Variation ID: 54840). This variant is found in the South Asian population with an allele frequency of 0.3% (99/30598 alleles, including 1 homozygote) in the Genome Aggregation Database. The lysine at codon 1110 is not highly conserved and does not occur in a known functional domain. Additionally, at least one functional study shows this variant is able to complement the growth defect of BRCA1 null cells, suggesting the variant does not impair BRCA1 function (Bouwman 2013). However, due to limited information, the clinical significance of this 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. Mannan AU et al. Detection of high frequency of mutations in a breast and/or ovarian cancer cohort: implications of embracing a multi-gene panel in molecular diagnosis in India. J Hum Genet. 2016 Jun;61(6):515-22. 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.
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000585901 SCV000591437 uncertain significance not provided no assertion criteria provided clinical testing The BRCA1 p.Lys1110del variant was identified in at least 1 of 55630 proband chromosomes from individuals or families with breast or ovarian cancer (Judkins 2005). The variant was also identified in dbSNP (ID: rs80358335) “With Uncertain significance allele”, the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 54 of 121128 chromosomes (frequency: 0.0004), or 54 individuals from a population of South Asian individuals, and none from European (Non-Finnish), East Asian, Other, African, Latino, or European (Finnish) individuals; and the ClinVar database (classified as a variant with uncertain significance by BIC, Ambry Genetics and Molecular Genetics Diagnostic Laboratory, CHEO and classification not provided by Invitae), and GeneInsight COGR database(3X, classified as “unknown significance” by 2 clinical laboratories, and unclassified by another). This variant is an in-frame deletion resulting in the removal of a lysine (Lys) residue at codon 1110; however, the impact of this alteration on BRCA1 protein function is not known. A cDNA-based functional complementation assay using BRCA1-deficient mouse embryonic stem cells, classified the variant as neutral by restoring cell proliferation and showing cisplatin sensitivity at levels similar to wild-type BRCA1 protein (Bouwman 2013). However, the impact of this alteration on other aspects of BRCA1 protein function is not known. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
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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