Submissions for variant NM_000059.4(BRCA2):c.4343A>T (p.Asn1448Ile)

dbSNP: rs762841458

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482410	SCV000564778	uncertain significance	not provided	2014-10-15	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.4343A>T at the cDNA level, p.Asn1448Ile (N1448I) at the protein level, and results in the change of an Asparagine to an Isoleucine (AAT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Asn1448Ile 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 Asparagine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asn1448Ile occurs at a position that is variable through vertebrates and is located in RAD51 domain (Roy 2012). 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 Asn1448Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064567	SCV001229477	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-06-22	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 418082). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is present in population databases (rs762841458, gnomAD 0.0009%). This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1448 of the BRCA2 protein (p.Asn1448Ile).
University of Washington Department of Laboratory Medicine, University of Washington	RCV003157560	SCV003850436	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).
Color Diagnostics, LLC DBA Color Health	RCV003157560	SCV004362048	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with isoleucine at codon 1448 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 been identified in 1/239056 chromosomes 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.
Ambry Genetics	RCV003157560	SCV005026432	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-31	criteria provided, single submitter	clinical testing	The p.N1448I variant (also known as c.4343A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 4343. The asparagine at codon 1448 is replaced by isoleucine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.