Submissions for variant NM_007294.4(BRCA1):c.4973C>A (p.Thr1658Asn)

dbSNP: rs1015073230

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000775095	SCV000909200	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with asparagine at codon 1658 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250286 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.
Invitae	RCV001042739	SCV001206440	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1658 of the BRCA1 protein (p.Thr1658Asn). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 630092). 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%. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 19683496). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001779075	SCV002014812	uncertain significance	not specified	2021-10-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.4973C>A (p.Thr1658Asn) results in a non-conservative amino acid change located in the BRCT Domain (IPR001357) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250286 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4973C>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. One publication reports experimental evidence evaluating an impact on protein phosphorylation (Johnson_2009), however, does not allow convincing conclusions about the variant effect. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV001042739	SCV002504993	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000775095	SCV002643469	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-24	criteria provided, single submitter	clinical testing	The p.T1658N variant (also known as c.4973C>A), located in coding exon 14 of the BRCA1 gene, results from a C to A substitution at nucleotide position 4973. The threonine at codon 1658 is replaced by asparagine, an amino acid with similar properties. This amino acid position is highly 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.