Submissions for variant NM_007294.4(BRCA1):c.4776C>G (p.Asn1592Lys)

gnomAD frequency: 0.00001  dbSNP: rs761925468

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162819	SCV000213302	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-04	criteria provided, single submitter	clinical testing	The p.N1592K variant (also known as c.4776C>G), located in coding exon 14 of the BRCA1 gene, results from a C to G substitution at nucleotide position 4776. The asparagine at codon 1592 is replaced by lysine, an amino acid with similar properties. This amino acid position is poorly 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.
GeneDx	RCV000590715	SCV000567561	likely benign	not provided	2019-01-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23289006)
Color Diagnostics, LLC DBA Color Health	RCV000162819	SCV000683213	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with lysine at codon 1592 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). A functional study has reported that this variant does not impact BRCA1 function in a mouse Brca1-deficient embryonic cell-based assays for homology-directed DNA repair and sensitivity to cisplatin and PARP inhibitor (PMID: 32546644). This variant has been detected in a breast cancer case-control meta-analysis in 0/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001232). A different nucleotide change resulting in the same protein missense mutation has been reported in an individual affected with breast cancer (PMID: 23289006). This variant has been identified in 3/251386 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000485047	SCV000699175	likely benign	not specified	2022-10-21	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4776C>G (p.Asn1592Lys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251386 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4776C>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence for causality (Beaubier_2019 and Saied_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (Bouwman_2020). These results showed no damaging effect of this variant on ability to complement BRCA1-deficient mouse embryonic stem cells in homologous recombination DNA repair (HRR) using cisplatin and olaparib sensitivity assays and a direct GFP HRR assay. HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, VUS (n=2) and Likely Benign (n=3). 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	RCV000616786	SCV000744609	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2015-09-21	criteria provided, single submitter	clinical testing
Invitae	RCV000697143	SCV000825739	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-07	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353751	SCV000591538	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA1 p.Asn1592Lys variant was identified in 1 of 242 proband chromosomes (frequency: 0.004) from individuals with breast cancer (Laraqui 2013); however, control chromosomes were not evaluated in this study. The variant was identified in three individuals in the Exome Aggregation Consortium (ExAC) database with allele counts of 1/67676 European (Non-Finnish), 1/11608 Latino, and 1/16628 South Asian alleles; however, this low number of observations and low frequency is not substantive enough to determine the prevalence of the variant in the general population and its relationship to disease. The variant was not identified in any other databases searched, including: dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, ClinVar, GeneInsight VariantWire, BIC or UMD. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; however, this is not very predictive of pathogenicity. The p.Asn1592 residue is not conserved in mammals and lower organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact of the variant amino acid to the protein. However, this information is not predictive enough to rule out 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 unknown significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000616786	SCV000733606	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing