Submissions for variant NM_007294.4(BRCA1):c.1824_1826del (p.Lys608del)

dbSNP: rs587781614

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129702	SCV000184503	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-11	criteria provided, single submitter	clinical testing	The c.1824_1826delGAA variant (also known as p.K608del) is located in coding exon 9 of the BRCA1 gene. This variant results from an in-frame GAA deletion at nucleotide positions 1824 to 1826. This results in the in-frame deletion of a lysine at codon 608. This alteration has been reported in Chinese and Czech high risk breast cancer populations (Zhong X et al. PLoS One, 2016 Jun;11:e0156789; Bhaskaran SP et al. Int J Cancer, 2019 08;145:962-973; Machackova E et al. Klin Onkol, 2019;32:51-71). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240694	SCV000265881	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587810	SCV000698890	uncertain significance	not provided	2017-07-03	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.1824_1826delGAA (p.Lys608del) variant involves the in-frame deletion of 3 nucleotides. One in silico tool predicts a polymorphism outcome for this variant. This variant was found in 4/121088 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. One reputable database cites the variant in an individual who also carries a pathogenic BRCA1 variant (BRCA1 c.3481_3491del [p.Glu1161PhefsX3]), suggesting the variant of interest is benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, the variant is classified as a VUS-possibly benign until additional information becomes available.
Invitae	RCV000637530	SCV000758993	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing	This variant, c.1824_1826del, results in the deletion of 1 amino acid(s) of the BRCA1 protein (p.Lys608del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs587781614, gnomAD 0.004%). This variant has been observed in individual(s) with breast cancer and/or suspected hereditary breast and ovarian cancer (PMID: 27257965, 34981296). ClinVar contains an entry for this variant (Variation ID: 141263). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant does not substantially affect BRCA1 function (PMID: 32546644). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587810	SCV000888851	uncertain significance	not provided	2018-01-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129702	SCV000912048	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of one amino acid, lysine, at codon 608 in the BRCA1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 27257965) and in an individual age 70 years or older without cancer in the FLOSSIES database. A multifactorial analysis has reported segregation, tumor pathology, co-occurrence and family history likelihood ratios for pathogenicity of 1.9083, 0.4, 1.0331 and 1.065, respectively (PMID: 31131967). This variant has been identified in 4/251062 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
CeGaT Center for Human Genetics Tuebingen	RCV000587810	SCV001249212	uncertain significance	not provided	2019-10-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818302	SCV002066938	uncertain significance	not specified	2017-12-05	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV003607243	SCV002581752	benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, BS3
GeneDx	RCV000587810	SCV003805380	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acids in a non-repeat region; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter protein structure/function; Published protein-based functional assays suggest no damaging effect: neutral in three homologous recombination repair complementation assays (Bouwman et al., 2020); Also known as 1943_1945delGAA; This variant is associated with the following publications: (PMID: 15343273, 20104584, 31131967, 32546644, 30702160, 31825140, 27257965)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000587810	SCV001550950	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Lys608del variant was identified in 1 of 1014 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer (Zhong 2016). The variant was also identified in dbSNP (ID: rs587781614) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Ambry Genetics, Invitae, Integrated Genetics/Laboratory Corporation of America, LMDC), Clinvitae, LOVD 3.0 (4x classified as VUS), and UMD-LSDB (1x as unclassified variant ) databases. In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (c.3481_3491del, p.Glu1161PhefsX3), increasing the likelihood that the p.Lys608del variant does not have clinical significance. The variant was not identified in GeneInsight-COGR, Cosmic, BIC Database, ARUP Laboratories, or Zhejiang University databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). This variant is an in-frame deletion resulting in the removal of a lysine (lys) residue at codon 608; the impact of this alteration on BRCA1 protein function is not known. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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 uncertain significance.
BRCAlab, Lund University	RCV002288627	SCV004244115	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2020-03-02	no assertion criteria provided	clinical testing