Submissions for variant NM_007294.4(BRCA1):c.4088C>T (p.Ser1363Leu)

dbSNP: rs398122680

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000216362	SCV000273842	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-15	criteria provided, single submitter	clinical testing	The p.S1363L variant (also known as c.4088C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 4088. The serine at codon 1363 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471702	SCV000549297	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-09	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 1363 of the BRCA1 protein (p.Ser1363Leu). This variant is present in population databases (rs398122680, gnomAD 0.0009%). 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: 91622). 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.
Color Diagnostics, LLC DBA Color Health	RCV000216362	SCV000909282	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-22	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000216362	SCV003851878	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).
All of Us Research Program, National Institutes of Health	RCV000077139	SCV004817711	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-15	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077139	SCV000108936	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2010-05-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500864	SCV000591486	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA1 p.Ser1363Leu variant was not identified in the literature but was identified in the ClinVar database, where it was classified as having uncertain significance by the Sharing Clinical Reports Project (derived from Myriad reports). The variant was not identified in any other databases searched, including dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, UMD, and the BIC database. The p.Ser1363 residue is conserved across mammals but not across lower organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.