Submissions for variant NM_000059.4(BRCA2):c.4321G>C (p.Glu1441Gln)

dbSNP: rs876659758

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223496	SCV000276563	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-09	criteria provided, single submitter	clinical testing	The p.E1441Q variant (also known as c.4321G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 4321. The glutamic acid at codon 1441 is replaced by glutamine, an amino acid with highly similar properties. This alteration was identified in 1/524 Portuguese HBOC families (Peixoto A et al. Clin. Genet.2015 Jul;88(1):41-8). This amino acid position is not well conserved in available vertebrate species. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001238191	SCV001410990	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1441 of the BRCA2 protein (p.Glu1441Gln). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24916970). ClinVar contains an entry for this variant (Variation ID: 232428). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800563	SCV002046565	uncertain significance	not specified	2021-01-07	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000223496	SCV003850417	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	RCV000223496	SCV004362047	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 1441 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a suspected hereditary breast and ovarian cancer family (PMID: 24916970). This variant has been identified in 1/242678 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.