Submissions for variant NM_000059.4(BRCA2):c.8293T>G (p.Cys2765Gly)

gnomAD frequency: 0.00001  dbSNP: rs768247528

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165936	SCV000216692	likely benign	Hereditary cancer-predisposing syndrome	2022-01-09	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000226067	SCV000283338	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 2765 of the BRCA2 protein (p.Cys2765Gly). This variant is present in population databases (rs768247528, gnomAD 0.02%). This missense change has been observed in individual(s) with renal clear cell carcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 186355). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on BRCA2 protein function. Experimental studies have shown that this missense change does not substantially affect BRCA2 function (PMID: 35736817, 37713444). 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.
GeneDx	RCV000478794	SCV000568100	uncertain significance	not provided	2023-08-15	criteria provided, single submitter	clinical testing	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); Published functional studies demonstrate no damaging effect: homology-directed repair activity comparable to wild-type (Hu et al., 2022); Also known as 8521T>G; This variant is associated with the following publications: (PMID: 29884841, 32377563, 12228710, 26689913, 31853058, 35736817)
Counsyl	RCV000239098	SCV000785678	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-10-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193319	SCV001362070	likely benign	not specified	2024-03-28	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8293T>G (p.Cys2765Gly) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 248566 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8293T>G has been reported in the literature in one individual affected with kidney renal clear cell carcinoma among 4,034 cases from The Cancer Genome Atlas cancer(Lu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one recent publication reports experimental evidence evaluating an impact on protein function (Sahu_2023). These results showed no damaging effect of this variant on homology directed repair (HDR) utilizing a statistical classifier based on cell fitness and their response to cisplatin and olaparib (lack of sensitivity to cisplatin and olaparib). Additionally other variants at the same codon, namely p.Cys2765Arg and p.Cys2765Ser are also categorized as functional and do not exhibit sensitivity to cisplatin and olaparib supporting a toleration for variants located at this codon. The following publications have been ascertained in the context of this evaluation (PMID: 26689913, 37713444). The ClinGen Sequence Variant Interpretation (SVI) working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). ClinVar contains an entry for this variant (Variation ID: 186355). Based on the evidence outlined above, the variant was classified as likely benign.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000226067	SCV001737451	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-05-27	criteria provided, single submitter	clinical testing	The BRCA2 c.8293T>G (p.Cys2765Gly) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/variant/13-32937632-T-G?dataset=gnomad_r2_1). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). It has also been identified in an individual with kidney renal clear cell carcinoma (PMID: 29684080). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting, PP3.
Sema4, Sema4	RCV000165936	SCV002531927	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000478794	SCV004220595	uncertain significance	not provided	2023-01-05	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/248566 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with kidney renal clear cell carcinoma (PMID: 26689913 (2015)). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV000239098	SCV004826009	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine at codon 2765 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown this variant does not impact homology-directed DNA repair activity (PMID: 35736817). This variant has been reported in individuals affected with renal cancer (PMID: 26689913, 37430226). This variant has been identified in 2/248566 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.
Baylor Genetics	RCV004567290	SCV005059201	uncertain significance	Familial cancer of breast	2023-11-04	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000239098	SCV000297565	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2013-07-01	no assertion criteria provided	clinical testing