ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs80358760
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Total submissions: 15
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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)

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