Submissions for variant NM_000059.4(BRCA2):c.7631G>A (p.Gly2544Asp)

dbSNP: rs397507926

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045271	SCV000073284	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-30	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 2544 of the BRCA2 protein (p.Gly2544Asp). This variant is present in population databases (rs397507926, gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 18006916, 26221963, 28664506, 28993434, 29263802, 32101877, 35918668). ClinVar contains an entry for this variant (Variation ID: 52373). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 protein function. 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.
Ambry Genetics	RCV000214936	SCV000274872	likely benign	Hereditary cancer-predisposing syndrome	2022-01-03	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	RCV000483279	SCV000566447	uncertain significance	not provided	2022-10-10	criteria provided, single submitter	clinical testing	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 7859G>A; Observed in individuals with a personal and/or family history of breast or ovarian cancer, as well as in unaffected controls (Ang et al., 2007; Yang et al., 2017; Wen et al., 2018; Wu et al., 2019); This variant is associated with the following publications: (PMID: 18006916, 12228710, 32101877, 28664506, 28993434)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483279	SCV004220567	uncertain significance	not provided	2023-09-21	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals affected with breast cancer (PMID: 18006916 (2007), 28664506 (2017), 28993434 (2018), 31706072 (2020), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)), and ovarian cancer (PMID: 32101877 (2019)). This variant has also been reported in unaffected individuals (PMID: 28993434 (2018), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250523	SCV002520834	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only
BRCAlab, Lund University	RCV003493426	SCV004243776	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing