Submissions for variant NM_000059.4(BRCA2):c.6347A>T (p.His2116Leu)

dbSNP: rs55953736

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219720	SCV000276262	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-31	criteria provided, single submitter	clinical testing	The p.H2116L variant (also known as c.6347A>T), located in coding exon 10 of the BRCA2 gene, results from an A to T substitution at nucleotide position 6347. The histidine at codon 2116 is replaced by leucine, an amino acid with similar properties. 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.
Color Diagnostics, LLC DBA Color Health	RCV000219720	SCV000683777	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-19	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with leucine at codon 2116 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 been reported in an individual affected with breast cancer in the Leiden Open-source Variation Database (https://databases.lovd.nl/shared/individuals/00095654). This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001071124	SCV001236412	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-08	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 2116 of the BRCA2 protein (p.His2116Leu). ClinVar contains an entry for this variant (Variation ID: 232197). 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. This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 21520333). This variant is not present in population databases (gnomAD no frequency).
CeGaT Center for Human Genetics Tuebingen	RCV001311839	SCV001502167	uncertain significance	not provided	2023-10-01	criteria provided, single submitter	clinical testing	BRCA2: PM2, BP1, BP4
University of Washington Department of Laboratory Medicine, University of Washington	RCV000219720	SCV003852450	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	RCV003997951	SCV004844249	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with leucine at codon 2116 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 been reported in an individual affected with breast cancer in the Leiden Open-source Variation Database (https://databases.lovd.nl/shared/individuals/00095654). This variant has not been identified 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.
GenomeConnect - Invitae Patient Insights Network	RCV001535551	SCV001749527	not provided	Fanconi anemia complementation group D1; Hereditary breast ovarian cancer syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 11-13-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.