Submissions for variant NM_007294.4(BRCA1):c.3782T>C (p.Leu1261Ser)

dbSNP: rs397507219

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129886	SCV000184703	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-28	criteria provided, single submitter	clinical testing	The p.L1261S variant (also known as c.3782T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 3782. The leucine at codon 1261 is replaced by serine, an amino acid with dissimilar 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.
Counsyl	RCV000031129	SCV000488280	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-02-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000709473	SCV000839247	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000031129	SCV001140543	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129886	SCV001340473	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-15	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 1261 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 not been reported in individuals affected with hereditary cancer in the literature. 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.
Invitae	RCV000709473	SCV001507931	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1261 of the BRCA1 protein (p.Leu1261Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 37548). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129886	SCV003847962	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).
Sharing Clinical Reports Project (SCRP)	RCV000031129	SCV000053728	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2008-08-15	no assertion criteria provided	clinical testing