Submissions for variant NM_000059.4(BRCA2):c.7930A>G (p.Asn2644Asp)

gnomAD frequency: 0.00001  dbSNP: rs431825360

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213312	SCV000276990	likely benign	Hereditary cancer-predisposing syndrome	2022-01-05	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	RCV000218919	SCV000279825	uncertain significance	not provided	2021-01-14	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8158A>G; Observed in individuals with BRCA2-related cancer (Loizidou 2017); Published functional studies suggest this variant has no impact on DSS1 interaction (Caleca 2019); This variant is associated with the following publications: (PMID: 27882536, 31131967, 30696104)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000808327	SCV000948433	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-05-24	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 30696104). 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. ClinVar contains an entry for this variant (Variation ID: 96862). This missense change has been observed in individual(s) with BRCA2-related conditions (PMID: 27882536). This variant is present in population databases (rs431825360, gnomAD 0.002%). This sequence change replaces asparagine, which is neutral and polar, with aspartic acid, which is acidic and polar, at codon 2644 of the BRCA2 protein (p.Asn2644Asp).
Mendelics	RCV000082983	SCV001139195	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2019-05-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213312	SCV001350574	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-22	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with aspartic acid at codon 2644 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. A functional study has shown that the variant has neutral impact on BRCA2/DSS1 interaction (PMID: 30696104). This variant has been reported in an individual affected with BRCA2-related cancer (PMID: 27882536). This variant has also been identified in 2/251304 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	RCV001194436	SCV001363996	uncertain significance	not specified	2019-04-02	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7930A>G (p.Asn2644Asp) results in a conservative amino acid change located in the helical domain (IPR015252), which is part of the DNA-binding domain and also mediates binding to DSS1 (Caleca 2019). Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246076 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.7930A>G, has been reported in the literature in individuals affected with tumors that belong to the HBOC spectrum (Azzollini 2016, Loizidou 2017), however one of these patients also carried another likely pathogenic BRCA2 variant that could explain the disease phenotype (Azzollini 2016). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that the variant did not affect the interaction with DSS1 (Caleca 2019), however as other functional studies, e.g. homology directed repair (HDR) assay, were not performed, this report does not allow convincing conclusions about the overall variant effect (Caleca 2019). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV001194436	SCV002071864	uncertain significance	not specified	2021-09-22	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BRCA2 gene demonstrated a sequence change, c.7930A>G, in exon 17 that results in an amino acid change, p.Asn2644Asp. This sequence change has been described in the gnomAD database with a frequency of 0.0018% in the non-Finnish European subpopulation (dbSNP rs431825360). This sequence change has been previously described in an individual with breast and/or ovarian cancer (PMID: 27882536). The p.Asn2644Asp change affects a moderately conserved amino acid residue located in a domain of the BRCA2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Asn2644Asp substitution. Experimental studies have demonstrated that this variant does not substantially impact the function of the BRCA2 protein (PMID: 30696104). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Asn2644Asp change remains unknown at this time.
Sharing Clinical Reports Project (SCRP)	RCV000082983	SCV000115057	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2012-04-17	no assertion criteria provided	clinical testing