Submissions for variant NM_000059.4(BRCA2):c.6316C>T (p.Leu2106Phe)

dbSNP: rs876660892

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215218	SCV000278679	uncertain significance	Hereditary cancer-predisposing syndrome	2015-09-29	criteria provided, single submitter	clinical testing	The p.L2106F variant (also known as c.6316C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 6316. The leucine at codon 2106 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6501 samples (13002 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and tolerated by PolyPhen and SIFT in silico analyses, respectively. Since supporting evidence is limited at this time, the clinical significance of p.L2106F remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000215218	SCV001356361	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-16	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 2106 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000215218	SCV003852420	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).