Submissions for variant NM_000059.4(BRCA2):c.3324G>T (p.Lys1108Asn)

dbSNP: rs1555283170

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572293	SCV000668829	uncertain significance	Hereditary cancer-predisposing syndrome	2017-07-17	criteria provided, single submitter	clinical testing	The p.K1108N variant (also known as c.3324G>T), located in coding exon 10 of the BRCA2 gene, results from a G to T substitution at nucleotide position 3324. The lysine at codon 1108 is replaced by asparagine, an amino acid with similar properties. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001264524	SCV001442724	uncertain significance	not specified	2020-10-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3324G>T (p.Lys1108Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 238854 control chromosomes (gnomAD). 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.3324G>T in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000572293	SCV003851860	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	RCV004001019	SCV004832809	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 1108 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA2-related disorders 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.