Submissions for variant NM_000059.4(BRCA2):c.8428A>G (p.Ser2810Gly)

gnomAD frequency: 0.00001  dbSNP: rs80359089

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129757	SCV000184564	likely benign	Hereditary cancer-predisposing syndrome	2019-12-06	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	RCV000657058	SCV000567893	uncertain significance	not provided	2018-03-22	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.8428A>G at the cDNA level, p.Ser2810Gly (S2810G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). Using alternate nomenclature, this variant would be defined as BRCA2 8656A>G. This variant has not, to our knowledge, been published in the literature as a germline variant; however it has been reported as a somatic variant in a lung tumor (Hovelson 2015). BRCA2 Ser2810Gly was not observed in large population cohorts (Lek 2016). BRCA2 Ser2810Gly is located in the DNA binding domain (Yang 2002). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA2 Ser2810Gly is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000129757	SCV000911248	likely benign	Hereditary cancer-predisposing syndrome	2017-02-13	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170975	SCV001333635	uncertain significance	Breast and/or ovarian cancer	2019-04-16	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657058	SCV001469724	uncertain significance	not provided	2020-05-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001314399	SCV001504932	likely benign	Hereditary breast ovarian cancer syndrome	2024-12-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000113930	SCV004845657	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-11-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005055547	SCV005725713	likely benign	not specified	2024-11-26	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8428A>G (p.Ser2810Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251384 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8428A>G in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. At least one publication reports experimental evidence evaluating an impact on protein function in vitro and found this variant to have a neutral impact in an HDR assay (example, Hart_2019, Richardson_2021). The HDR assay qualifies as a standardized gold-standard assay on the basis of the updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) Working Group (Brnich_2019). ClinGen SVI now recognizes benign functional evidence as sufficient for likely benign (Tavtigian_2018). ClinVar contains an entry for this variant (Variation ID: 52584). Based on the evidence outlined above, the variant was classified as likely benign.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113930	SCV000147361	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000484281	SCV000592192	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2, p.Ser2810Gly variant was identified in the literature (Karchin 2008) and dbSNP database “With Uncertain significance allele.” This variant also was identified in the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 1 individual of European (Non-Finnish) descent. The variant was not found in populations of South Asians, European (Non-Finnish), East Asian, African, Latino, and other individuals. The variant was also identified in Clinvar database and classified as a variant of uncertain significance by BIC and Ambry Genetics; no classification was provided by Invitae. The p.Ser2810Gly variant was identified in BRCA Share UMD Database 1X and classified as unknown. In UMD the variant was identified with a co-occurring pathogenic BRCA1 variant (BRCA1: c.3481_3491del, p.Glu1161PhefsX3), increasing the likelihood that the p.Ser2810Gly variant does not have clinical significance. The variant was identified 1X in BIC database with unknown clinical importance and 1X in LOVD as neutral. The p.Ser2810 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% chance that the variant creates the loss of a cryptic 3’ acceptor splice site. However, this information is not predictive enough to assume pathogenicity. In addition, likelihood ratio analysis predicted the variant does not impair protein function and was determined neutral (Karchin 2008). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.