Submissions for variant NM_000059.4(BRCA2):c.5390C>G (p.Ala1797Gly)

gnomAD frequency: 0.00001  dbSNP: rs80358760

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000044649	SCV000072662	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1797 of the BRCA2 protein (p.Ala1797Gly). This variant is present in population databases (rs80358760, gnomAD 0.003%). This missense change has been observed in individual(s) with personal and/or family history of breast and/or ovarian cancer (PMID: 30254663). ClinVar contains an entry for this variant (Variation ID: 51852). 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.
Ambry Genetics	RCV000167078	SCV000217906	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-04	criteria provided, single submitter	clinical testing	The p.A1797G variant (also known as c.5390C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 5390. The alanine at codon 1797 is replaced by glycine, an amino acid with similar properties. This variant was identified in one family undergoing BRCA1/2 testing (Zuntini R et al. Front Genet, 2018 Sep;9:378). This amino acid position is not well 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000113425	SCV000743307	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000113425	SCV000785356	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-07-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284430	SCV001470223	uncertain significance	not provided	2023-05-25	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individual(s) with breast and or ovarian cancer (PMID: 30254663 (2018)). In a large-scale breast cancer association study, the variant was observed in a breast cancer case and in unaffected individuals (PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.000026 (3/113490 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.
GeneDx	RCV001284430	SCV002099642	uncertain significance	not provided	2022-02-14	criteria provided, single submitter	clinical testing	Identified in individuals with breast or ovarian cancer (Zutini 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5618C>G; This variant is associated with the following publications: (PMID: 27930734, 30254663)
Sema4, Sema4	RCV000167078	SCV002536130	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-07	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000167078	SCV003847211	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).
Color Diagnostics, LLC DBA Color Health	RCV000167078	SCV004362104	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-08	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 1797 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 an individual with a personal or family history of breast and/or ovarian cancer (PMID: 34572941). This variant has also been reported in a breast cancer case-control meta-analysis in 1/60465 cases and 4/53457 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001468). This variant has been identified in 3/251078 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
All of Us Research Program, National Institutes of Health	RCV000113425	SCV004846570	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-05-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 1797 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 an individual with a personal or family history of breast and/or ovarian cancer (PMID: 34572941). This variant has also been reported in a breast cancer case-control meta-analysis in 1/60465 cases and 4/53457 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001468). This variant has been identified in 3/251078 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may not be associated with disease, additional studies are necessary 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)	RCV000113425	SCV000146606	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001284430	SCV001554269	uncertain significance	not provided		no assertion criteria provided	clinical testing	The BRCA2 C.5390C>G variant has not been reported in the literature nor previously identified by our laboratory. It is reported in BIC as a variant with unknown pathogenicity, and also listed in dbDNP (rs-id: rs80358760) identified from a clinical source with no frequency information provided. This is a missense alteration, which changes the residue Ala to Gly in the protein sequence coded by exon 11 (p.Ala1797Gly), which may have an impact on the function, however the SIFT program predicts this variant to be benign. In summary, based on the above information alone the clinical significance of this variant cannot be determined with certainty at the current time. Classified under ACMG-4
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV001284430	SCV001906155	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001284430	SCV001955425	likely benign	not provided		no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000113425	SCV004228409	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)