Submissions for variant NM_000059.4(BRCA2):c.3965A>C (p.Asn1322Thr)

dbSNP: rs80358646

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165691	SCV000216429	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-01	criteria provided, single submitter	clinical testing	The p.N1322T variant (also known as c.3965A>C), located in coding exon 10 of the BRCA2 gene, results from an A to C substitution at nucleotide position 3965. The asparagine at codon 1322 is replaced by threonine, an amino acid with similar 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.
GeneDx	RCV000483586	SCV000566175	uncertain significance	not provided	2023-07-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 4193A>C; This variant is associated with the following publications: (PMID: 31911673, 32377563, 31131967, 29884841)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770722	SCV000902201	uncertain significance	Breast and/or ovarian cancer	2017-01-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165691	SCV000903955	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780038	SCV000917053	uncertain significance	not specified	2018-11-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3965A>C (p.Asn1322Thr) results in a non-conservative amino acid change located in the BRCA2 repeat region, between the second and third repeat (IPR002093) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 224534 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.3965A>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483586	SCV001133777	uncertain significance	not provided	2019-02-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001325825	SCV001516832	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-07-03	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 1322 of the BRCA2 protein (p.Asn1322Thr). This variant is not present in population databases (gnomAD no frequency). 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: 51575). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165691	SCV003848563	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	RCV000113253	SCV004845247	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113253	SCV000146347	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000483586	SCV002037381	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000483586	SCV002038114	likely benign	not provided		no assertion criteria provided	clinical testing