Submissions for variant NM_000059.4(BRCA2):c.1666A>G (p.Asn556Asp)

dbSNP: rs587781794

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130055	SCV000184882	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-12	criteria provided, single submitter	clinical testing	The p.N556D variant (also known as c.1666A>G), located in coding exon 9 of the BRCA2 gene, results from an A to G substitution at nucleotide position 1666. The asparagine at codon 556 is replaced by aspartic acid, an amino acid with highly similar properties. In a study of 359 breast cancer patients and 66 ovarian cancer patients in the Hakka population in southern China, this alteration was identified in a patient with breast cancer (Wu H et al. Hum Hered, 2019 Feb;84:160-169). In another study, this variant was reported in 3/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). This amino acid position is poorly 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.
GeneDx	RCV000587388	SCV000279802	uncertain significance	not provided	2023-08-14	criteria provided, single submitter	clinical testing	Identified in individuals with breast or ovarian cancer and in unaffected controls (Wu et al., 2019; Dorling et al., 2021; Zhang et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 1894A>G; This variant is associated with the following publications: (PMID: 25348012, 22505045, 32101877, 31131967, 33471991, 35918668)
Invitae	RCV000543145	SCV000635173	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 556 of the BRCA2 protein (p.Asn556Asp). This variant is present in population databases (rs587781794, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 32101877). ClinVar contains an entry for this variant (Variation ID: 141498). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001549274	SCV000694556	uncertain significance	not specified	2021-07-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.1666A>G (p.Asn556Asp) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251222 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1666A>G has been reported in the literature in individuals affected with breast cancer (e.g. Wu_2019, Dorling_2021) but it has also been reported in controls (e.g. Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic variant has been reported (BRCA2 c.4093delT, p.Cys1365ValfsX9; UMD), providing supporting evidence for a benign role. Experimental evidence demonstrated the variant does not affect splicing (Houdayer_2012). Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely benign. A recent publication involving the ENIGMA network of collaborators (Parsons_2019) assigned a classification of uncertain significance based on likelihood ratios (LRs) for pathogenicity estimated from clinical data of co-occurrence, family history and bioinformatic predictions; however, no evidence was provided for independent assessment. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587388	SCV000888990	uncertain significance	not provided	2023-04-07	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000004 (1/251222 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 32101877 (2019) and 33471991 (2021), http://databases.lovd.nl/shared/genes/BRCA2), as well as healthy individuals (PMID: 33471991 (2021), http://databases.lovd.nl/shared/genes/BRCA2). A functional study using a minigene assay reported that the variant had no effect on splicing (PMID: 22505045 (2012)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000130055	SCV000903458	likely benign	Hereditary cancer-predisposing syndrome	2017-05-01	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000130055	SCV003851561	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).
PreventionGenetics, part of Exact Sciences	RCV003945145	SCV004760119	uncertain significance	BRCA2-related condition	2023-12-04	criteria provided, single submitter	clinical testing	The BRCA2 c.1666A>G variant is predicted to result in the amino acid substitution p.Asn556Asp. This variant was reported in 4 individuals with breast cancer (Dorling et al 2021. PubMed ID: 33471991; Wu et al 2019. PubMed ID: 32101877) and in 2 control individuals (Dorling et al 2021. PubMed ID: 33471991). Experimental evidence demonstrated the variant does not affect splicing (Houdayer et al 2012. PubMed ID: 22505045). A recent publication involving the ENIGMA network of collaborators (Parsons et al 2019. PubMed ID: 31131967) assigned a classification of uncertain significance to this variant. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250568	SCV002520938	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only