ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8524C>T (p.Arg2842Cys) (rs80359104)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045544 SCV000073557 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2842 of the BRCA2 protein (p.Arg2842Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed on the opposite chromosome (in trans) from pathogenic variants in families with features of Fanconi anemia, but without personal history of cancer (PMID: 32354836, external communication). Moreover, this variant has been reported to be homozygous in an individual affected with primary ovarian insufficiency, but without other Fanconi anemia features (PMID: 32482800). This variant is also known as c.8752C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 52610). Experimental studies have shown that this variant has intermediate homologous recombination activity (PMID: 29988080, 23108138, 32482800, 32354836). Also, it has an intermediate effect on chromosomal breaks levels, cell proliferation rates and RAD51 foci formation in the patient’s derived cells (PMID: 32482800). 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 RCV000656805 SCV000210475 likely pathogenic not provided 2021-05-24 criteria provided, single submitter clinical testing Observed in the heterozygous state in individuals with personal or family history of breast cancer, but also in healthy controls (Wen 2018, Peker Eyuboglu 2020); Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 8752C>T; This variant is associated with the following publications: (PMID: 29394989, 28993434, 29988080, 32719484, 31825140, 32482800, 33150793, 33807840, 33054725, 29884841, 32354836, 31851867, 30455982, 23108138, 19043619, 11309337, 10923033, 12228710, 28664449, 24123850, 11948123, 27378171, 24323938, 27176796, 27194814, 28726806, 32042831)
Ambry Genetics RCV000165225 SCV000215939 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-21 criteria provided, single submitter clinical testing The p.R2842C variant (also known as c.8524C>T), located in coding exon 19 of the BRCA2 gene, results from a C to T substitution at nucleotide position 8524. The arginine at codon 2842 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has also been identified in two independent sets of siblings with Fanconi Anemia confirmed in trans with two different truncating BRCA2 variants (Ambry internal data). In a study with breast cancer patients and healthy controls, this alteration was not detected in 2575 breast cancer patients but was detected in 1/2809 controls (Wen WX et al. J. Med. Genet. 2018 Feb;55(2):97-103). A mouse embryonic stem cell survival assay and multiple homology-directed DNA repair (HDR) assays demonstrated p.R2842C to have intermediate functionality, with a probability of pathogenicity of 0.987 and a probability of neutrality of 0.013 (Guidugli L et al. Cancer Res. 2013 Jan 1;73(1):265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 02;102(2):233-248; Mesman RLS et al. Genet. Med. 2019 02;21:293-302). Of note, this alteration is also designated as 8752C>T in published literature. 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 variant is likely to be pathogenic. 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.
Department of Pathology and Molecular Medicine,Queen's University RCV000212277 SCV000588119 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656805 SCV000600811 uncertain significance not provided 2019-09-16 criteria provided, single submitter clinical testing
Mendelics RCV000045544 SCV000838879 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000045544 SCV000897864 pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-31 criteria provided, single submitter clinical testing Data used in classification: This variant has been seen in trans with an established pathogenic variant in BRCA2 in a UK case of Fanconi D1 (chromosome breakage studies abnormal, BRCA2 ubiquitination function intermediate). Reduced level of BRCA2 protein on Western blot giving gene-phenotype specificity (PP4). BRCA2 was fully screened in this case (PM3). The variant is deleterious on the HR assay described by Guidugli et al (Couch laboratory), p=0.99 in 2013 and p=0.987 (2018) (PS3). Delirious on AlignGVGD, SIFT, Polyphen (PP3). Located in DNA binding domain (PM1_sup). In the GNOMAD NFE population of 63,369 individuals, the frequency of this variant is 1 (PM2-sup). Additional Information (not included in classification): There are additional reports of this variant in [ClinVar (5) , BIC (1), UMD (5) and BRCA2 LOVD (1)]. Reported several times in ENIGMA in HBOC families (verbal report). Comment: We have classified this as pathogenic but of intermediate penetrance based on (i) lack of cancer in index Fanconi case at age 10 (ii) Couch assay of 0.987 (all positive controls were p>0.99) (iii) BRCA2 ubiquitination function intermediate (iii) lack of family history in large pedigree for UK Fanconi case.
Color Health, Inc RCV000165225 SCV000911453 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-07 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 2842 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). Splice site prediction tools and RNA studies suggest that this variant may not impact RNA splicing (PMID: 24123850). Experimental functional studies have demonstrated partial or intermediate effects on homology directed repair (HDR; PMID: 23108138, 24323938, 29884841, 29394989, 29988080, 32354836, 32482800) and intermediate sensitivity to mitomicin C (MMC) or PARP inhibitors (PMID: 32354836), but normal sensitivity to cisplatin and normal complementation of a BRCA2-null cell lethal phenotype (PMID: 29988080). It has also been shown to be defective in replication fork protection of stalled replication forks during interstrand crosslink (ICL) repair, but without an increase in chromosomal breakage (PMID: 32354836). This variant has been reported compound heterozygous in 2 related siblings diagnosed with atypical Fanconi anemia (PMID: 32354836), but also homozygous in an individual with primary ovarian insufficiency without any personal or family history of cancer (PMID: 32482800). It has additionally been reported in a control individual from a breast cancer case-control study (PMID: 28993434) and an individual considered at-risk for hereditary breast cancer (PMID: 31851867). Lastly, it was also found to co-occur with a BRCA1 pathogenic variant in an individual in the BIC database (PMID: 10923033). This variant has been identified in 3/282388 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Although there is evidence of a hypomorphic role for this variant in an autosomal recessive, atypical Fanconi Anemia phenotype, the available evidence is insufficient to conclusively determine the role in autosomal dominant hereditary cancer. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212277 SCV000916900 uncertain significance not specified 2019-08-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8524C>T (p.Arg2842Cys) results in a non-conservative amino acid change located in the Tower domain (IPR015205) 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 1.2e-05 in 256724 control chromosomes (gnomAD). The variant, c.8524C>T, has been reported in the literature in a case-control study, to be found in 1/2809 controls, but was absent in 2575 breast cancer cases (Wen 2018). c.8524C>T has been also reported to co-occur with another pathogenic variant (BRCA1 c.135-1G>T, in the BIC database), providing supporting evidence for a benign role. However, several functional studies reported that this variant result in an intermediate activity in homology-directed DNA repair (HDR) assay (Mesman_2018, Hart_2019, Guidugli_2018). Eight other clinical diagnostic laboratories have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (1x pathogenic, 1x likely benign and 6x uncertain significance). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Mendelics RCV000077443 SCV001139221 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286194 SCV001472726 uncertain significance none provided 2019-11-07 criteria provided, single submitter clinical testing The BRCA2 c.8524C>T; p.Arg2842Cys variant (rs80359104) is reported in the literature in a single healthy control (Wen 2018). This variant is reported in ClinVar (Variation ID: 52610), and is only observed on three alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 2842 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show a reduction in homology-directed repair activity (Guidugli 2018, Mesman 2019). However, given the lack of clinical data and limited functional data, the significance of the p.Arg2842Cys variant is uncertain at this time. References: Guidugli L et al. Assessment of the Clinical Relevance of BRCA2 Missense Variants by Functional and Computational Approaches. Am J Hum Genet. 2018 Feb 1;102(2):233-248. Mesman RLS et al. The functional impact of variants of uncertain significance in BRCA2. Genet Med. 2019 Feb;21(2):293-302. Wen WX et al. Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia. J Med Genet. 2018 Feb;55(2):97-103.
Sharing Clinical Reports Project (SCRP) RCV000077443 SCV000109241 likely benign Breast-ovarian cancer, familial 2 2011-02-09 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077443 SCV000147390 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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