Submissions for variant NM_000059.4(BRCA2):c.4919A>G (p.His1640Arg)

dbSNP: rs373483754

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000583557	SCV000688906	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001223708	SCV001395867	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-07-03	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1640 of the BRCA2 protein (p.His1640Arg). This variant is present in population databases (rs373483754, 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: 491287). 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.
Ambry Genetics	RCV000583557	SCV002644481	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-20	criteria provided, single submitter	clinical testing	The c.4919A>G (p.H1640R) alteration is located in exon 11 (coding exon 10) of the BRCA2 gene. This alteration results from a A to G substitution at nucleotide position 4919, causing the histidine (H) at amino acid position 1640 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000583557	SCV003852208	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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586807	SCV005077518	uncertain significance	not specified	2024-04-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.4919A>G (p.His1640Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246440 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4919A>G has been reported in the literature without strong evidence for causality (Delahunty_2022). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 491287). Based on the evidence outlined above, the variant was classified as uncertain significance.