ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5020A>G (p.Ser1674Gly) (rs80358725)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129669 SCV000184467 benign Hereditary cancer-predisposing syndrome 2015-06-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),in silico models in agreement (benign),Other strong data supporting benign classification
Breast Cancer Information Core (BIC) (BRCA2) RCV000113368 SCV000146521 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000129669 SCV000911691 likely benign Hereditary cancer-predisposing syndrome 2015-07-16 criteria provided, single submitter clinical testing
Counsyl RCV000113368 SCV000488261 uncertain significance Breast-ovarian cancer, familial 2 2016-02-12 criteria provided, single submitter clinical testing
GeneDx RCV000588519 SCV000278855 uncertain significance not provided 2018-07-05 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5020A>G at the cDNA level, p.Ser1674Gly (S1674G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant, also known as BRCA2 5248A>G using alternate nomenclature, was observed in one woman with bilateral breast cancer (Borg 2010), and another woman with breast cancer diagnosed at age 50 or younger (Pal 2015). BRCA2 Ser1674Gly was observed at an allele frequency of 0.05% (11/23,678) in individuals of African ancestry in large population cohorts (Lek 2016). This variant is located within the BRC5 domain and the RAD51 and POLH binding domains (Cole 2011, Roy 2012, Buisson 2014). While protein-based in silico analysis supports that this variant does not alter protein structure/function, splicing models predict the creation of a novel cryptic splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA2 Ser1674Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588519 SCV000694820 uncertain significance not provided 2017-01-02 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5020A>G (p.Ser1674Gly) variant involves the alteration of a non-conserved nucleotide is predicted to be benign by 3/5 in silico tools. This variant was found in 2/118544 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.0002074 (2/9644). This frequency is lower than the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). In literature, this variant has been reported in three breast cancer patients without strong evidence for pathogenicity (Borg_2011, Kim_2015, Pal_2015) and has been classified as VUS with inclination of benign outcome. It has also been reported in several individuals undergoing BRCA1/2 testing in ClinVar and UMD. In two HBOC patients reported by BIC and eight individuals reported by UMD, no other deleterious variants were found. Clinical diagnostic laboratories have provided conflicting interpretations of pathogenicity in ClinVar, as benign (1) as well as uncertain significance (3). Taken together, this variant is currently classified as Variant of Uncertain Significance.
Invitae RCV000044539 SCV000072552 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces serine with glycine at codon 1674 of the BRCA2 protein (p.Ser1674Gly). The serine residue is weakly conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs80358725, ExAC 0.02%). This variant has been reported in individuals affected with breast cancer (PMID: 20104584, 26287763). This variant has also been observed in an individual affected with ovarian cancer (Invitae). However, in that individual, a pathogenic allele was also identified in BRCA1, which suggests that this c.5020A>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 51756). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000218378 SCV000600620 uncertain significance not specified 2017-06-14 criteria provided, single submitter clinical testing

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