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

gnomAD frequency: 0.00001  dbSNP: rs80359104

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000045544	SCV000073557	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2842 of the BRCA2 protein (p.Arg2842Cys). This variant is present in population databases (rs80359104, gnomAD 0.008%). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 32354836, 32482800; external communication). This variant is also known as c.8752C>T. ClinVar contains an entry for this variant (Variation ID: 52610). 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 not expected to disrupt BRCA2 protein function with a negative predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA2 function (PMID: 23108138, 29988080, 32354836, 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	2024-08-09	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 (PMID: 28993434, 31851867, 33471991, 35264596); In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8752C>T; This variant is associated with the following publications: (PMID: 27378171, 28664449, 11309337, 28726806, 32042831, 23108138, 27194814, 27176796, 24323938, 11948123, 24123850, 29988080, 12228710, 10923033, 29394989, 28993434, 19043619, 30455982, 32482800, 31851867, 32354836, 29884841, 33054725, 33807840, 33150793, 33977503, 32719484, 31825140, 35665744, 36106376, 36754117, Sflomos2023[article], 35264596, 36721989, 33471991, Bahsi2020[case report], 34326862, Baldo2024[article], 36099812)
Ambry Genetics	RCV000165225	SCV000215939	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-13	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. 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). In another study, this variant was reported in 3/60,466 breast cancer cases and in 2/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration has been identified in two independent sets of siblings with Fanconi anemia confirmed in trans with two different truncating BRCA2 variants, and one set is described as having a milder presentation (Rickman KA et al. Genes Dev, 2020 06;34:832-846; Ambry internal data). In addition, this alteration has been observed as homozygous in a Turkish woman who presented with primary ovarian insufficiency and who did not have overt clinical features of Fanconi anemia or personal or family history of cancer but who did demonstrate intermediate molecular effects including chromosomal breaks, cell proliferation and RAD51 foci formation (Caburet S et al. J Med Genet, 2020 Jun;). A mouse embryonic stem cell survival assay and multiple homology-directed DNA repair (HDR) assays also demonstrated an intermediate functional effect for p.R2842C (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, this alteration is predicted to be deleterious by in silico analysis. 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 as well as in a homozygous patient without Fanconi anemia, it is likely to 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	2020-11-05	criteria provided, single submitter	clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London	RCV000045544	SCV000897864	pathogenic	Hereditary breast 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 Diagnostics, LLC DBA Color Health	RCV000165225	SCV000911453	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-09	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 in compound heterozygous state in 2 siblings diagnosed with atypical Fanconi anemia, and in compound heterozygous state in 1 unrelated individual diagnosed with Fanconi anemia; all 3 individuals with no evidence of bone marrow failure or malignancy at time of reporting despite family history of cancer (PMID: 32354836, ClinVar: SCV000897864.1). The variant was also reported in homozygous state in an individual with primary ovarian insufficiency without any personal or family history of BRCA2-associated cancer (PMID: 32482800). Cells homozygous for this variant showed intermediate defects compared with cells from non-carriers and cells from individuals with Fanconi anemia, in terms of MMC-induced chromosomal breaks, cell proliferation rate and radiation-induced RAD51 foci formation (PMID: 32482800). This variant has been detected in two breast cancer case-control studies in 0/2575 cases and 1/2809 unaffected individuals (PMID: 28993434) and in 3/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000340). This variant has also been reported in an individual considered at-risk for hereditary breast cancer (PMID: 31851867) and in two individuals affected with BRCA2-associated cancers and/or relevant family history (Color internal data). 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	2022-06-27	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. c.8524C>T has been reported in the literature as a VUS in individuals with breast cancer (example, Wen_2017, Chan_2018). Additionally, two recent studies have reported this as a hypomorphic BRCA2 variant in a homozygous individual with primary ovarian insufficiency without cancer or Fanconi anaemia traits (Caburet_2020) and as a compound heterozygous genotype with a BRCA2 frameshift variant (c.2330dupA) in two female siblings from the International Fanconi Anemia Registry (IFAR) reported as having an atypical presentation of Fanconi anemia with a multitude of congenital abnormalities and mildly elevated levels of chromosomal breakage at birth (Rickman_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant(s) have been reported in the BIC database (BRCA1 c.135-1G>T), providing supporting evidence for a benign role. Multiple publications report experimental evidence evaluating an impact on protein function (example, Mesman_2018, Guidugli_2018, Hart_2019, Caburet_2020, Rickman_2020). The most pronounced variant effect results in intermediate levels of homology directed repair (HDR) activity. Multiple 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 (VUS, n=7; Pathogenic/Likely pathogenic with a risk factor verbiage (n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Mendelics	RCV000077443	SCV001139221	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2024-08-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656805	SCV001472726	uncertain significance	not provided	2023-11-13	criteria provided, single submitter	clinical testing	The BRCA2 c.8524C>T; p.Arg2842Cys variant (rs80359104) is reported in the literature in individuals affected with breast cancer (Bhai 2021, Gao 2020, Guindalini 2022), but also in healthy controls (Wen 2018). Additionally, this variant is reported in the homozygous state in an individual with no cancer or Fanconi anemia traits (Caburet 2020), and in the compound heterozygous state in two siblings with atypical Fanconi anemia (Rickman 2020). This variant is reported in ClinVar (Variation ID: 52610), and is found in the general population with an overall allele frequency of 0.0011% (3/282388 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.843). Functional analyses of the variant protein show intermediate homology-directed repair activity (Caburet 2020, Guidugli 2018, Mesman 2019, Rickman 2020). Due to conflicting information, the clinical significance of this variant is uncertain at this time. References: Bhai P et al. Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach. Front Genet. 2021 Jul 13;12:698595. PMID: 34326862. Caburet S et al. Homozygous hypomorphic BRCA2 variant in primary ovarian insufficiency without cancer or Fanconi anaemia trait. J Med Genet. 2020 Jun 1:jmedgenet-2019-106672. PMID: 32482800. Gao X et al. Comprehensive profiling of BRCA1 and BRCA2 variants in breast and ovarian cancer in Chinese patients. Hum Mutat. 2020 Mar;41(3):696-708. PMID: 31825140. 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. PMID: 29394989. Guindalini RSC et al. Detection of germline variants in Brazilian breast cancer patients using multigene panel testing. Sci Rep. 2022 Mar 9;12(1):4190. PMID: 35264596. Mesman RLS et al. The functional impact of variants of uncertain significance in BRCA2. Genet Med. 2019 Feb;21(2):293-302. PMID: 29988080. Rickman KA et al. Distinct roles of BRCA2 in replication fork protection in response to hydroxyurea and DNA interstrand cross-links. Genes Dev. 2020 Jun 1;34(11-12):832-846. PMID: 32354836. 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. PMID: 28993434.
MGZ Medical Genetics Center	RCV000077443	SCV002580328	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-03-22	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473424	SCV004211804	uncertain significance	Familial cancer of breast	2023-10-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077443	SCV004846031	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	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 in compound heterozygous state in 2 siblings diagnosed with atypical Fanconi anemia, and in compound heterozygous state in 1 unrelated individual diagnosed with Fanconi anemia; all 3 individuals with no evidence of bone marrow failure or malignancy at time of reporting despite family history of cancer (PMID: 32354836, ClinVar: SCV000897864.1). The variant was also reported in homozygous state in an individual with primary ovarian insufficiency without any personal or family history of BRCA2-associated cancer (PMID: 32482800). Cells homozygous for this variant showed intermediate defects compared with cells from non-carriers and cells from individuals with Fanconi anemia, in terms of MMC-induced chromosomal breaks, cell proliferation rate and radiation-induced RAD51 foci formation (PMID: 32482800). This variant has been detected in two breast cancer case-control studies in 0/2575 cases and 1/2809 unaffected individuals (PMID: 28993434) and in 3/60466 cases and 2/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000340). This variant has also been reported in an individual considered at-risk for hereditary breast cancer (PMID: 31851867) and in two individuals affected with BRCA2-associated cancers and/or relevant family history (Color internal data). 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.
Laboratory of Medical Genetics Unit, Bambino Gesù Children's Hospital	RCV004689433	SCV005093809	likely pathogenic	BRCA2-related cancer predisposition		criteria provided, single submitter	clinical testing	The c.8524C>T variant (p.Arg2842Cys) is located in coding exon 19 of the BRCA2 gene. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. The arginine 2842 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been found in two breast cancer case-control studies in 0/2575 cases and 1/2809 unaffected individuals (PMID: 28993434) and in 3/60466 cases and 2/53461 unaffected individuals (PMID: 33471991). This variant has been detected in two independent sets of siblings with Fanconi anemia confirmed in trans with two different truncating BRCA2 variants. Functional studies have demonstrated partial or intermediate effects on homology directed repair (PMID: 23108138, 24323938) 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).
Sharing Clinical Reports Project (SCRP)	RCV000077443	SCV000109241	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-02-09	flagged submission	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077443	SCV000147390	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2003-12-23	no assertion criteria provided	clinical testing