ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7964A>G (p.Gln2655Arg) (rs80359024)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212265 SCV000210453 likely pathogenic not provided 2018-03-07 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7964A>G at the cDNA level, p.Gln2655Arg (Q2655R) at the protein level, and results in the change of a Glutamine to an Arginine (CAA>CGA). Using alternate nomenclature, this variant would be defined as BRCA2 8192A>G. Ruud et al. (2001) reported a patient with Fanconi anemia who passed away following a diagnosis of medulloblastoma and resultant chemotherapy toxicity. Follow-up studies on archived tissue by Bodd et al. (2010) revealed compound heterozygosity for BRCA2 Gln2655Arg, present in her father, and a BRCA2 nonsense variant, present in her mother, who had a family history of breast and ovarian cancer. In addition, functional studies of this variant showed decreased homology directed repair activity (Guidugli 2018). BRCA2 Gln2655Arg was not observed in large population cohorts (Lek 2016). BRCA2 Gln2655Arg is located in the DNA binding domain and the DSS1 contacting residue (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 evidence, we consider BRCA2 Gln2655Arg to be likely pathogenic.
Ambry Genetics RCV000510118 SCV000608034 pathogenic Hereditary cancer-predisposing syndrome 2020-01-22 criteria provided, single submitter clinical testing The p.Q2655R pathogenic mutation (also known as c.7964A>G), located in coding exon 16 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7964. The glutamine at codon 2655 is replaced by arginine, an amino acid with highly similar properties. This alteration was detected in trans with a BRCA2 pathogenic nonsense mutation in an archived medulloblastoma sample from a deceased girl with Fanconi Anemia (Ruud E et al. Acta Paediatr. 2001 May;90:580-3; Bodd TL et al. Acta Paediatr. 2010 Nov;99:1741-3). This alteration is also defective in a homology directed DNA repair (HDR) assay (Guidugli L et al. Am. J. Hum. Genet. 2018 02;102(2):233-248). Based on internal structural analysis this alteration is likely to disrupt DSS1 binding and is predicted to be as destabilizing to the local structure as other known pathogenic variants (Yang H et al. Science 2002 Sep;297:1837-48; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this alteration is interpreted as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
Counsyl RCV000113846 SCV000785547 uncertain significance Breast-ovarian cancer, familial 2 2017-09-06 criteria provided, single submitter clinical testing
Color Health, Inc RCV000510118 SCV000911874 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-07 criteria provided, single submitter clinical testing
Mendelics RCV000113846 SCV001139196 likely pathogenic Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000113846 SCV001428744 likely pathogenic Breast-ovarian cancer, familial 2 2020-01-07 criteria provided, single submitter clinical testing
Invitae RCV001378206 SCV001575727 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-11-01 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 2655 of the BRCA2 protein (p.Gln2655Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Fanconi anemia (PMID: 20608899). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 52450). 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 expected to disrupt BRCA2 protein function. This variant has been reported to affect BRCA2 protein function (PMID:29394989, 29884841). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Breast Cancer Information Core (BIC) (BRCA2) RCV000113846 SCV000147229 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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