Submissions for variant NM_007294.4(BRCA1):c.5191G>A (p.Glu1731Lys)

dbSNP: rs397507244

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000549475	SCV000636016	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1731 of the BRCA1 protein (p.Glu1731Lys). 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: 91641). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). 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	RCV001023693	SCV001185606	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-23	criteria provided, single submitter	clinical testing	The p.E1731K variant (also known as c.5191G>A), located in coding exon 17 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5191. The glutamic acid at codon 1731 is replaced by lysine, an amino acid with similar properties. One functional study found that this nucleotide substitution is non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). This alteration was detected in 1/76 individuals of Armenian descent with either a family history of cancer or breast cancer before the age of 40 (Moradian MM et al. Hum Genome Var, 2021 Feb;8:9). This alteration was also observed with an allele frequency of 0 in 7,051 unselected female breast cancer patients and 0.00009 in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV001547117	SCV001766747	likely pathogenic	not provided	2020-01-31	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: classified as non-functional based on a saturation genome editing (SGE) assay measuring cell growth (Findlay 2018); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 5310G>A; This variant is associated with the following publications: (PMID: 30209399, 27923043)
Sharing Clinical Reports Project (SCRP)	RCV000077158	SCV000108955	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2011-07-18	no assertion criteria provided	clinical testing
Center of Medical Genetics and Primary Health Care	RCV001090053	SCV000987235	uncertain significance	Familial cancer of breast	2020-06-12	no assertion criteria provided	research	ACMG Guidelines 2015 criteria The BRCA1 variant p.Glu1731Lys is in exon 19 in the BRCT domain (S1642-1736V aa). This domain of about 95 amino acids is found in a large variety of proteins involved in DNA repair, recombination and cell cycle control (Bork et al., 1997). It is found in a mutational hotspot including 34 pathogenic missense, nonsense, and frameshift variants (PM1 Pathogenic Moderate). The allele frequency in GnomAD exomes is 0.0000159 which is less the threshold 0.0001for recessive gene BRCA1, and the variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). 8 pathogenic predictions from DANN, EIGEN, FATHMM-MKL, M-CAP, MVP, MutationTaster, REVEL and SIFT versus 3 benign predictions from DEOGEN2, MutationAssessor and PrimateAI support its deleterious effect (PP3 Pathogenic Supporting). In this study this variant was found in a 51-year-old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Variant of Unknown Significance.
Brotman Baty Institute, University of Washington	RCV000077158	SCV001241844	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro