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

dbSNP: rs80358335

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001079725	SCV000076158	benign	Hereditary breast ovarian cancer syndrome	2024-01-28	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	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000585901	SCV000321429	likely benign	not provided	2022-07-29	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Counsyl	RCV000112065	SCV000488064	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 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	RCV003323379	SCV000699018	likely benign	not specified	2023-07-07	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3328_3330delAAG (p.Lys1110del) results in an in-frame deletion that is predicted to remove one amino acids from the encoded protein. The variant allele was found at a frequency of 0.00039 in 250772 control chromosomes, predominantly at a frequency of 0.0032 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is above 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3328_3330delAAG has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, without strong evidence for causality, and was additionally found in an unaffected individual in the literature (Mannan_2016). Experimental evidence including an HDR assay evaluating impact on protein function showed no damaging effect of this variant (Bouwman_2013, Bouwman_2020). The following publications have been ascertained in the context of this evaluation (PMID: 22486713, 23867111, 32546644, 25036526, 16267036, 26911350, 29785135, 28263838, 19370767). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=7) and VUS (n=6). Based on the evidence outlined above, 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, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	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	RCV000585901	SCV001470964	uncertain significance	not 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.
Molecular Endocrinology Laboratory, Christian Medical College	RCV000112065	SCV002030307	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001079725	SCV002504997	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132199	SCV002538200	likely benign	Hereditary cancer-predisposing syndrome	2022-03-11	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000585901	SCV003830126	uncertain significance	not provided	2021-02-09	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585901	SCV004140627	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	BRCA1: PM4:Supporting, BS3:Supporting, BS2
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112065	SCV000144718	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000112065	SCV000297599	likely benign	Breast-ovarian cancer, familial, susceptibility to, 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	RCV000585901	SCV002034939	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000585901	SCV002035917	likely benign	not provided		no assertion criteria provided	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000112065	SCV003927173	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-05-05	no assertion criteria provided	clinical testing	We detected an in-frame deletion in the BRCA1 gene (c.3328_3330delAAG) which results in the deletion of the amino acid lysine at position 1110. This mutation is considered as a variant of unknown significance.