Submissions for variant NM_000059.4(BRCA2):c.6500T>C (p.Leu2167Ser)

dbSNP: rs730881543

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160112	SCV000210391	uncertain significance	not provided	2014-05-09	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.6500T>C at the cDNA level, p.Leu2167Ser (L2167S) at the protein level, and results in the change of a Leucine to a Serine (TTA>TCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu2167Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Leu2167Ser occurs at a position that is moderately conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Leu2167Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001850261	SCV002162135	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-11	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 2167 of the BRCA2 protein (p.Leu2167Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 30362333). ClinVar contains an entry for this variant (Variation ID: 182225). 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 BRCA2 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.
Ambry Genetics	RCV002362850	SCV002659188	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-17	criteria provided, single submitter	clinical testing	The p.L2167S variant (also known as c.6500T>C), located in coding exon 10 of the BRCA2 gene, results from a T to C substitution at nucleotide position 6500. The leucine at codon 2167 is replaced by serine, an amino acid with dissimilar properties. This alteration has been reported in a Southern Mediterranean individual with sporadic breast cancer (Belaiba F et al. Asian Pac. J. Cancer Prev., 2018 Oct;19:2963-2972). This amino acid position is not well 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002362850	SCV003852587	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).