Submissions for variant NM_000059.4(BRCA2):c.6441C>G (p.His2147Gln)

gnomAD frequency: 0.00001  dbSNP: rs80358879

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044948	SCV000072961	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-29	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2147 of the BRCA2 protein (p.His2147Gln). This variant is present in population databases (rs80358879, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 27328445). ClinVar contains an entry for this variant (Variation ID: 38045). 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	RCV000496559	SCV000600701	uncertain significance	not specified	2016-11-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001025273	SCV001187432	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-03	criteria provided, single submitter	clinical testing	The p.H2147Q variant (also known as c.6441C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 6441. The histidine at codon 2147 is replaced by glutamine, an amino acid with highly similar properties. In one study, this variant was reported in 1/19 individuals diagnosed with triple negative breast cancer (Spugnesi L et al. Genes Chromosomes Cancer, 2016 12;55:915-924). This alteration was also identified in an individual considered high risk for breast and/or ovarian cancer (Foglietta J et al. Genes (Basel), 2020 08;11:). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001025273	SCV003852528	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).
Sharing Clinical Reports Project (SCRP)	RCV000031627	SCV000054234	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-05-01	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031627	SCV000146851	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496559	SCV000587845	uncertain significance	not specified	2014-01-31	no assertion criteria provided	research