Submissions for variant NM_000059.4(BRCA2):c.5228G>A (p.Ser1743Asn)

gnomAD frequency: 0.00003  dbSNP: rs587782714

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132192	SCV000187272	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-23	criteria provided, single submitter	clinical testing	The p.S1743N variant (also known as c.5228G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 5228. The serine at codon 1743 is replaced by asparagine, an amino acid with highly similar properties. This variant was identified in 1/157 individuals selected according to NCCN criteria for hereditary breast cancer and tested with a panel of 33 genes related to hereditary cancer (de Souza Timoteo AR et al. Breast Cancer Res. Treat., 2018 Dec;172:637-646). This alteration was also detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477559	SCV000296547	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0002 (7/34340 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an affected individual with breast cancer from Brazil (PMID: 30159786 (2018)). 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.
Counsyl	RCV000239058	SCV000488213	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-01-24	criteria provided, single submitter	clinical testing
Invitae	RCV000637755	SCV000759232	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1743 of the BRCA2 protein (p.Ser1743Asn). This variant is present in population databases (rs587782714, gnomAD 0.02%). This missense change has been observed in individual(s) with a personal or family history of breast cancer (PMID: 30159786, 35264596). ClinVar contains an entry for this variant (Variation ID: 142783). 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.
Mendelics	RCV000637755	SCV000838810	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132192	SCV000911398	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000239058	SCV001139109	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000132192	SCV002533935	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-22	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132192	SCV003847097	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	RCV000505841	SCV004122589	uncertain significance	not specified	2023-10-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5228G>A (p.Ser1743Asn) 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 2.8e-05 in 249568 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5228G>A has been reported in the literature in individuals affected with Breast Cancer (example, Guindalini_2022, deSouzaTimoteo_2018), without strong evidence for causality. These report(s) do 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. The following publications have been ascertained in the context of this evaluation (PMID: 35264596, 30159786). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS=8, Likely benign=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003917426	SCV004733606	uncertain significance	BRCA2-related condition	2024-01-03	criteria provided, single submitter	clinical testing	The BRCA2 c.5228G>A variant is predicted to result in the amino acid substitution p.Ser1743Asn. This variant was reported as a variant of uncertain significance in a Brazilian breast cancer cohort study (de Souza Timoteo et al. 2018. PubMed ID: 30159786; Supp. Table 3 Guindalini RSC et al 2022. PubMed ID: 35264596). This variant is reported in 0.020% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32913720-G-A) and is listed in ClinVar as uncertain or likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/142783/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.