Submissions for variant NM_000059.4(BRCA2):c.3506A>C (p.Asn1169Thr)

dbSNP: rs1194031580

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001779481	SCV002014956	uncertain significance	not specified	2021-10-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3506A>C (p.Asn1169Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250872 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.3506A>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV003158942	SCV003846663	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).
Ambry Genetics	RCV003158942	SCV003855580	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	The p.N1169T variant (also known as c.3506A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 3506. The asparagine at codon 1169 is replaced by threonine, an amino acid with similar properties. This amino acid position is conserved. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV005057611	SCV005718871	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-24	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1169 of the BRCA2 protein (p.Asn1169Thr). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1321387). 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.