Submissions for variant NM_007294.4(BRCA1):c.2397T>A (p.Asn799Lys)

dbSNP: rs80357203

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000047824	SCV000075837	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 799 of the BRCA1 protein (p.Asn799Lys). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 54556). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV000164929	SCV000215618	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	The p.N799K variant (also known as c.2397T>A), located in coding exon 9 of the BRCA1 gene, results from a T to A substitution at nucleotide position 2397. The asparagine at codon 799 is replaced by lysine, an amino acid with similar properties. This alteration was reported in a cohort of 55630 patients who underwent BRCA1 gene sequencing at a commercial laboratory and was classified as a variant of unknown significance (Judkins T et al. Cancer Res, 2005 Nov;65:10096-103). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768615	SCV000324812	uncertain significance	Breast and/or ovarian cancer	2015-11-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000111842	SCV000488092	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2015-12-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164929	SCV000683031	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-05	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 799 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a multifactorial analysis with likelihood ratios for pathogenicity based on tumor pathology, co-occurrence with a pathogenic covariant and family history of 0.2856, 1.2975 and 2.4402, respectively (PMID: 31131967). This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587218	SCV000698947	uncertain significance	not provided	2017-04-14	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.2397T>A (p.Asn799Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). The variant of interest is absent in the large, broad control population, ExAC in 121334 control chromosomes. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. This variant is reported in UMD-BRCA1 in 4 patients and in 2 as co-occurring with a variant classified by UMD as pathogenic (c.5144G>A; p.Ser171Asn). At this time LCA did not classify this variant and as such these co-occurrences were not included. Because of the paucity of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587218	SCV000888864	uncertain significance	not provided	2021-07-21	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000164929	SCV003847702	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111842	SCV000144406	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2002-05-29	no assertion criteria provided	clinical testing