Submissions for variant NM_000059.4(BRCA2):c.5272A>G (p.Asn1758Asp)

gnomAD frequency: 0.00001  dbSNP: rs80358750

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044624	SCV000072637	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000113413	SCV000488238	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000589423	SCV000567407	uncertain significance	not provided	2024-09-09	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer, one of whom also had a family history of breast cancer and tumor showing loss of heterozygosity (PMID: 33471991, 28868023); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Also known as 5500A>G; This variant is associated with the following publications: (PMID: 31131967, 10923033, 24817641, 29884841, 33471991, 31853058, 32377563, 28868023)
Ambry Genetics	RCV000562802	SCV000668581	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-20	criteria provided, single submitter	clinical testing	The p.N1758D variant (also known as c.5272A>G), located in coding exon 10 of the BRCA2 gene, results from an A to G substitution at nucleotide position 5272. The asparagine at codon 1758 is replaced by aspartic acid, an amino acid with highly similar properties. This variant has been identified in a familial breast cancer patient whose tumor demonstrated LOH (Sorscher S et al. Case Rep Oncol Jul;10:634-637). This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 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.
Color Diagnostics, LLC DBA Color Health	RCV000562802	SCV000688925	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-21	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 1758 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 at least three individual affected with breast cancer (PMID: 28868023, 33471991; Leiden Open Variation Database DB-ID BRCA2_008322; Color internal data). This variant has been identified in 1/250312 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387744	SCV000694852	uncertain significance	not specified	2023-09-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5272A>G (p.Asn1758Asp) results in a conservative amino acid change in the encoded protein sequence. Four of four 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 250312 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5272A>G has been reported in the literature in at least one individual affected with breast cancer (Sorscher_2017). The report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. One co-occurrence with another pathogenic variant has been reported (BRCA1 c.5207T>C, p.Val1736Ala, internal data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 28868023). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=6) and likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589423	SCV000887847	uncertain significance	not provided	2024-08-22	criteria provided, single submitter	clinical testing	The BRCA2 c.5272A>G (p.Asn1758Asp) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 28868023 (2017), 33471991 (2021)), as well as individuals referred for hereditary breast/ovarian cancer genetic testing (PMID: 31853058 (2020)). It is also described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000004 (1/250312 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000589423	SCV001716156	uncertain significance	not provided	2019-04-18	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000562802	SCV003847131	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	RCV004803193	SCV004846554	uncertain significance	BRCA2-related cancer predisposition	2024-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 1758 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 at least three individual affected with breast cancer (PMID: 28868023, 33471991; Leiden Open Variation Database DB-ID BRCA2_008322; Color internal data). This variant has been identified in 1/250312 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.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113413	SCV000146586	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing