ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8350C>T (p.Arg2784Trp) (rs80359075)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045487 SCV000073500 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 2784 of the BRCA2 protein (p.Arg2784Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs80359075, ExAC 0.001%). This variant has been observed in individuals affected with breast, ovarian, and lung cancer (PMID: 16683254, 27616075, 30032850). This variant may be associated with reduced penetrance of hereditary breast and ovarian cancer syndrome based on statistical analysis (external communication). In addition, this variant has been observed in individuals with Fanconi anemia (PMID: 21520333, external communication). 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: 38155). Experimental studies have shown that this missense change disrupts BRCA2 homology-directed DNA break repair activity, but it has not been shown to affect centrosome amplification (PMID: 18451181, 23108138, 29884841,29988080). 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.
Ambry Genetics RCV000131691 SCV000186727 pathogenic Hereditary cancer-predisposing syndrome 2020-01-22 criteria provided, single submitter clinical testing The p.R2784W pathogenic mutation (also known as c.8350C>T), located in coding exon 18 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8350. The arginine at codon 2784 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration was identified in several breast and ovarian cancer cohorts and segregates with disease (van der Hout AH et al. Hum. Mutat. 2006 Jul;27:654-66; Gómez García EB et al. Breast Cancer Res. 2009 Feb;11:R8; Kraus C et al. Int. J. Cancer. 2017 Jan;140(1):95-102; Ambry internal data). This alteration was also observed in trans with a pathogenic BRCA2 alteration in a patient with Fanconi Anemia (personal communication). Several independent assays find this variant non-functional including multiple homology-directed DNA repair assays; a centriole amplification assay and a mouse embryonic stem cell complementationa ssay (Farrugia DJ et al. Cancer Res. 2008 May;68:3523-31; Guidugli L et al. Cancer Res. 2013 Jan;73:265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Mesman RLS et al. Genet. Med. 2018 Jul). Internal structural analysis indicates that this variant is likely to disrupt BRCA2 binding to DSS1, a protein that has been shown to stabilize BRCA2 and participate in its clinically relevant functions (Yang H et al. Science 2002 Sep;297:1837-48). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is interpreted as a disease-causing mutation.
GeneDx RCV000392114 SCV000329141 likely pathogenic not provided 2018-11-21 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8350C>T at the cDNA level, p.Arg2784Trp (R2784W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). Using alternate nomenclature, this variant would be defined as BRCA2 8578C>T. This variant has been identified in individuals with a personal and/or family history of breast and/or ovarian cancer (van der Hout 2006, Gomez Garcia 2009, Brandao 2011). While BRCA2 Arg2784Trp did not induce centrosome amplification, this variant displayed reduced homologous recombination repair activity in multiple homology-directed DNA break repair assays, which have been shown to have high sensitivity and specificity for determining pathogenicity of BRCA2 missense variants in the DNA-binding domain (Farrugia 2008, Guidugli 2013, Mesman 2018). In addition, a multifactorial analysis combining in silico and functional data classified this variant as pathogenic (Guidugli 2018). BRCA2 Arg2784Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Arg2784Trp is located within the DSS1 contacting residues of 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 the currently available evidence, we consider BRCA2 Arg2784Trp to be a likely pathogenic variant.
Color Health, Inc RCV000131691 SCV000911858 likely pathogenic Hereditary cancer-predisposing syndrome 2021-01-25 criteria provided, single submitter clinical testing This missense variant replaces arginine with tryptophan at codon 2784 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). This variant is reported as defective in homology-directed DNA repair assays (PMID: 18451181, 29394989, 29988080) and complementation of BRCA2-deficient mouse embryonic stem cell (PMID: 29988080). This variant has been observed in individuals and families affected with breast or ovarian cancer ( 18451181, 16683254, 19200354, 21638052, 27153395, 31409081, 31843900, 31742824) and an individual affected with breast and colon cancer (PMID: 21638052). This variant has been identified in 2/251430 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000392114 SCV001133931 likely pathogenic not provided 2020-06-16 criteria provided, single submitter clinical testing The best available variant frequency is uninformative because there are too few occurrences in population data. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Occurs in a single case with an alternate molecular basis for disease.
Mendelics RCV000031738 SCV001139212 likely pathogenic Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001171399 SCV001363256 uncertain significance not specified 2020-12-11 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8350C>T (p.Arg2784Trp) results in a non-conservative amino acid change located in the BRCA2, OB1 domain 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 251430 control chromosomes. c.8350C>T has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (van der Hout_2006, Farrugia_2008, Garcia_2009, Vail_2015, Kraus_2017, daCosta_2019, Machackova_2019, Shao_2020). The variant has also been reported in an individual with lung cancer (Donner_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Several publications report experimental evidence evaluating an impact on protein function (Farrugia_2008, Guidugli_2013, Guidugli_2018, Mesman_2019). The results showed that this variant significantly affected homology directed repair activity, however, it did not result in centriole or centrosome amplification. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments, five classified the variant as likely pathogenic/pathogenic while two classified the variant as VUS. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000045487 SCV001478299 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-10 criteria provided, single submitter curation Data used in classification: This variant is predicted deleterious on AlignGVGD (class: C65), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (20.3) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). This variant is classified on ClinVar as likely pathogenic by accredited USA diagnostic laboratory GeneDx, 2017 (PP5_sup). Data not used in classification: The variant was observed in 1 independent UK family undergoing clinical diagnostic BRCA1/BRCA2 testing for HBOC according to diagnostic criteria, the denominator of which dataset of clinical testing was 16,600. Case control comparison against ethnically matched population data (1/16,600 in familial cases against 1/55,836 gnomAD NFE controls) 2-sided Fishers exact: pexact= 0.4. The frequency of this variant is 2/67,272 individuals (remainder of the gnomAD population).
Sharing Clinical Reports Project (SCRP) RCV000031738 SCV000054345 uncertain significance Breast-ovarian cancer, familial 2 2012-09-25 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031738 SCV000147329 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
King Laboratory,University of Washington RCV001267731 SCV001251302 uncertain significance Breast-ovarian cancer, familial 2; Hereditary breast and ovarian cancer syndrome 2019-09-01 no assertion criteria provided research This variant yielded normal BRCA2 splicing when tested on RNA from a patient’s lymphoblast cell line using cBROCA. cBROCA evaluates changes in splicing due to germline mutations from participants' RNA and does not evaluate changes that alter function at the protein level. This variant might have an effect at the protein level.

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