Submissions for variant NM_000059.4(BRCA2):c.5341G>A (p.Asp1781Asn)

gnomAD frequency: 0.00001  dbSNP: rs183478654

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132288	SCV000187373	likely benign	Hereditary cancer-predisposing syndrome	2024-03-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000589648	SCV000278859	uncertain significance	not provided	2025-03-13	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: ability to rescue cell lethality and lack of sensitivity to DNA damaging agents (PMID: 33293522); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5569G>A; This variant is associated with the following publications: (PMID: 26543556, 33359728, 29884841, 32377563, 30630528, 33293522, 31853058)
Counsyl	RCV000409214	SCV000489111	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-08-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589648	SCV000694861	uncertain significance	not provided	2017-08-03	criteria provided, single submitter	clinical testing	Variant summary: The BRCA2 c.5341G>A (p.Asp1781Asn) variant involves the alteration of a non-conserved nucleotide and 3/4 in silico tools (SNPsandGO not captured due to low reliability index) predict a benign outcome. However, these predictions have yet to be functionally assessed. This variant was found in 2/120702 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). A publication cites the variant in an affected individual with limited information (ie, lack of co-occurrence and cosegregation data)(Dean_BRCA_GigaScience_2015). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Therefore, due to the limited available information (ie, lack of clinical and/or functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637785	SCV000759264	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-30	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 1781 of the BRCA2 protein (p.Asp1781Asn). This variant is present in population databases (rs183478654, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer (PMID: 26543556, 33359728). ClinVar contains an entry for this variant (Variation ID: 142848). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects BRCA2 function (PMID: 33293522). 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	RCV000132288	SCV002053693	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-18	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 1781 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). A functional study in mouse embryonic stem cells reported that this variant did not impact cell survival or sensitivity to DNA-damaging agents (PMID: 33293522). This variant has been reported in an individual affected with breast cancer (PMID: 26543556) and in an individual affected with colorectal cancer (PMID: 33359728). This variant has been identified in 3/250662 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132288	SCV003847173	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589648	SCV004219684	uncertain significance	not provided	2022-05-10	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000087 (3/34536 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with breast cancer (PMID: 26543556 (2015)) and in an individual with young-onset colorectal cancer (PMID: 33359728 (2022)). 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.
All of Us Research Program, National Institutes of Health	RCV000409214	SCV004846559	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with asparagine at codon 1781 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). A functional study in mouse embryonic stem cells reported that this variant did not impact cell survival or sensitivity to DNA-damaging agents (PMID: 33293522). This variant has been reported in an individual affected with breast cancer (PMID: 26543556) and in an individual affected with colorectal cancer (PMID: 33359728). This variant has been identified in 3/250662 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.