ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8360G>A (p.Arg2787His) (rs80359078)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212273 SCV000210470 uncertain significance not provided 2018-02-14 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8360G>A at the cDNA level, p.Arg2787His (R2787H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). Using alternate nomenclature, this variant would be defined as BRCA2 8588G>A. This variant has been observed in an individual with breast cancer whose tumor showed loss of heterozygosity, in an individual with a personal history of a Lynch syndrome associated cancer and/or polyps, but also in a woman with ovarian cancer who also carried a BRCA1 pathogenic variant (Riahi 2015, Yurgelun 2015, Riahi 2016, Eoh 2017). While the homology-directed repair activity of this variant was slightly reduced compared to the wild-type, it was comparable to other known benign and likely benign variants (Guidugli 2013, Guidugli 2018). Published multifactorial likelihood models have predicted this variant to be likely benign based on tumor pathology, clinical histories and family studies (Lindor 2012, Guidugli 2013). BRCA2 Arg2787His was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Arg2787His is located in the DSS1 contacting residues of the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors?and evolutionary conservation, support a deleterious effect. Despite some suggestion of neutrality, we consider BRCA2 Arg2787His to be a variant of uncertain significance.
Ambry Genetics RCV000214554 SCV000274666 likely benign Hereditary cancer-predisposing syndrome 2019-10-29 criteria provided, single submitter clinical testing Conflicting evidence
Counsyl RCV000031739 SCV000488563 likely benign Breast-ovarian cancer, familial 2 2016-04-28 criteria provided, single submitter clinical testing
Color Health, Inc RCV000214554 SCV000689119 uncertain significance Hereditary cancer-predisposing syndrome 2020-11-13 criteria provided, single submitter clinical testing This missense variant replaces arginine with histidine at codon 2787 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies reported that this variant protein to have homology-directed DNA repair activities similar to wild-type (PMID: 29394989, 29988080) intermediate in function (PMID: 23108138). This variant has been reported in two suspected hereditary breast and ovarian cancer families (PMID: 27211102, 29310832) and in an individual suspected of Lynch syndrome (PMID: 25980754). This variant also has been reported to have segregation likelihood ratio of 1.995 and tumor pathology likelihood ratio of 0.655 (PMID: 31131967). This variant has been identified in 10/282802 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.
Mendelics RCV000031739 SCV001139214 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174961 SCV001338441 uncertain significance not specified 2020-04-30 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8360G>A (p.Arg2787His) results in a non-conservative amino acid change located in the BRCA2, OB1 domain (IPR015187) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.5e-05 in 282802 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (3.5e-05 vs 0.00075), allowing no conclusion about variant significance. Multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Lindor_2012, Guidugli_2013). c.8360G>A has been reported in the literature in individuals affected with breast cancer and/or ovarian cancer as well as in one individual with a history of LS-associated cancer and/or colorectal polyps (Riahi_2015, Yurgelun_2015, Eoh_2017). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In addition, at least one co-occurrence with another pathogenic variant has been reported (BRCA1 c.928C>T, p.Gln310Ter), providing supporting evidence for a benign role (Eoh_2017). Functional studies report this variant has no impact on protein function based on HDR assay results (Guidugli_2012, Hart_2018, Mesman_2018). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212273 SCV001469718 uncertain significance not provided 2019-09-30 criteria provided, single submitter clinical testing
Invitae RCV001442600 SCV001645551 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-20 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031739 SCV000054346 uncertain significance Breast-ovarian cancer, familial 2 2012-02-29 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031739 SCV000147334 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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