Submissions for variant NM_000059.4(BRCA2):c.5590G>A (p.Asp1864Asn)

gnomAD frequency: 0.00001  dbSNP: rs587781536

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129542	SCV000184322	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-08	criteria provided, single submitter	clinical testing	The p.D1864N variant (also known as c.5590G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5590. The aspartic acid at codon 1864 is replaced by asparagine, an amino acid with highly similar properties. This alteration was identified in a 66-year-old Chinese male diagnosed with with esophageal squamous cell carcinoma who had no family history of cancer but did have a personal history of tobacco use (Zhong L et al. Asian Pac. J. Cancer Prev. 2011;12:1771-6). This alteration was also identified in multiple individuals diagnosed with breast and/or ovarian cancer (Cao WM et al. BMC Cancer. 2016 Feb;16:64; Zhong X et al. PLoS ONE. 2016 Jun;11:e0156789; Kim HN et al. Chonnam Med J, 2019 May;55:99-103; Zhunussova G et al. Front Oncol, 2019 Aug;9:673). 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.
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University	RCV000240784	SCV000265937	uncertain significance	Breast neoplasm	2015-11-01	criteria provided, single submitter	research
Invitae	RCV000456720	SCV000549768	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 1864 of the BRCA2 protein (p.Asp1864Asn). This variant is present in population databases (rs587781536, gnomAD 0.01%). This missense change has been observed in individual(s) with breast and/or ovarian cancer and in an individual with esophageal squamous cell carcinoma and esophageal squamous cell carcinoma (PMID: 22126563, 26852015, 27257965, 30415210, 30725392, 31161121, 31907386). ClinVar contains an entry for this variant (Variation ID: 141155). 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.
Color Diagnostics, LLC DBA Color Health	RCV000129542	SCV000906111	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 1864 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 multiple individuals affected with breast or ovarian cancer (PMID: 26852015, 27257965, 28111427, 30725392, 31161121, 33078592, 35402282), an individual affected with esophageal cancer (PMID: 22126563), and two individuals affected with colorectal cancer (PMID: 31428572). In a large breast cancer case-control meta analysis, this variant was reported in 3/60466 cases and 2/53461 unaffected controls; (OR=1.326 (95%CI 0.222 to 7.938); Leiden Open Variation Database DB-ID BRCA2_006877 (PMID: 33471991)). This variant has been identified in 3/246000 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.
Mendelics	RCV000989040	SCV001139116	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271414	SCV002556188	uncertain significance	not specified	2022-06-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5590G>A (p.Asp1864Asn) results in a conservative amino acid change located in the BRCA2 repeat (IPR002093) of 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 1.9e-05 in 268772 control chromosomes (gnomAD, Dong_2021). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5590G>A has been reported in the literature in individuals affected with esophageal cancer (Zhong_2011), and Breast/Ovarian cancer (Zhong_2016, Cao_2016, Park_2017, So_2019, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A multi-factorial analysis of ethnic Koreans by Lee_2018 produced a combined likelihood ratio of 0.023, leading the authors to conclude the variant is "likely benign". To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129542	SCV003848933	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).