Submissions for variant NM_000059.4(BRCA2):c.9875C>T (p.Pro3292Leu)

gnomAD frequency: 0.00009  dbSNP: rs56121817

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077478	SCV001161630	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000108
Invitae	RCV000195340	SCV000073921	benign	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131346	SCV000186321	benign	Hereditary cancer-predisposing syndrome	2021-03-04	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000513762	SCV000210519	likely benign	not provided	2020-09-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32444794, 31409081, 31509718, 30199306, 30287823, 30400234, 29802286, 31131967, 29126202, 28814288, 28477318, 27907908, 27211102, 26566862, 26577449, 24372583, 25589618, 26740942, 19540122, 24323938, 18593900, 15800615, 20104584, 23704879)
Eurofins Ntd Llc (ga)	RCV000513762	SCV000228418	uncertain significance	not provided	2014-12-23	criteria provided, single submitter	clinical testing
Michigan Medical Genetics Laboratories, University of Michigan	RCV000077478	SCV000267833	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000513762	SCV000296514	likely benign	not provided	2023-03-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000077478	SCV000383806	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services, Illumina	RCV000301085	SCV000383807	likely benign	Fanconi anemia complementation group D1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000045908	SCV000538504	uncertain significance	not specified	2016-10-20	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 Br.Ca. patient, functional study shows potential impact (not enough to go above VUS); ClinVar: 4 VUS, 2 LB
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513762	SCV000610403	uncertain significance	not provided	2017-03-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000045908	SCV000695277	benign	not specified	2019-01-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9875C>T (p.Pro3292Leu) results in a non-conservative amino acid change in 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 8.9e-05 in 247930 control chromosomes (gnomAD and publication). This frequency is not significantly higher than expected for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer (8.9e-05 vs 0.00075) however, the variant could still represent a rare polymorphism. c.9875C>T has been reported in the literature in individuals affected with breast and/or ovarian cancer, sarcoma, metastatic castration-resistant prostate cancer and pancreatic ductal adenocarcinoma (Abulkhair_2018, Diaz-Zabala_2018, Takeuchi_2018, Annala_2017, Barrios_2017, Ballinger_2016, Chao_2016, Francies_2015, Riahi_2015, Borg_2010). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variants have been reported (BRCA2 c.3922G>T, p.Glu1308X; BRCA2 c.9117G > A, p.Pro3039Pro; BRCA2 9502delT, c.9274delT, p.Tyr3092Ilefs)(Barrios_2017, ClinVar, BIC database), providing supporting evidence for a benign role. Furthermore, in a Fanconi anemia patient carrying this variant, variants were detected in FANCC gene (c.37C>T, p.Gln13X; c.1069C>T, p.Gln357X) (Nicchia_2015), providing supporting evidence for a benign role in this specific case. Experimental evidence evaluating an impact on protein function reported the variant as not being disruptive to the interaction of BRCA2 with RAD51, RAD51 foci formation was not significantly impaired following DNA damage induction and no significant increase in sensitivity to mitomycin C and etoposide was observed (Esashi _2005, Hucl _2008). Nine ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance (5x), likely benign (3x) and once as benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000195340	SCV000838912	benign	Hereditary breast ovarian cancer syndrome	2023-08-22	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000513762	SCV000885091	uncertain significance	not provided	2017-11-14	criteria provided, single submitter	clinical testing	The BRCA2 c.9875C>T; p.Pro3292Leu variant is described in the medical literature in individuals and families with breast cancer (Borg 2010, Francies 2015, Riahi 2015, Chao2016). However, the variant was also published in an individual with Fanconi anemia who also carried two nonsense variants in the FANCC gene (Nicchia 2015). The variant is listed in the ClinVar database as both a variant of uncertain significance and as likely benign/benign (Variation ID: 52910). The variant is listed in the dbSNP variant database (rs56121817) and in the Genome Aggregation Database in 20/245936 alleles. The proline at this position is conserved across species and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. While in silico studies imply this variant may impact function (Tram 2013) functional studies show that this variant has no effect on at least some functions (Eashi 2005, Hucl 2008). Considering available information, this variant cannot be classified with certainty. References: Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Chao A et al. Prevalence and clinical significance of BRCA1/2 germline and somatic mutations in Taiwanese patients with ovarian cancer. Oncotarget. 2016 Dec 20;7(51):85529-85541. Esashi F et al. CDK-dependent phosphorylation of BRCA2 as a regulatory mechanism for recombinational repair. Nature. 2005 Mar 31;434(7033):598-604. Francies FZ et al. BRCA1, BRCA2 and PALB2 mutations and CHEK2 c.1100delC in different South African ethnic groups diagnosed with premenopausal and/or triple negative breast cancer. BMC Cancer. 2015 Nov 17;15:912. Hucl T et al. A syngeneic variance library for functional annotation of human variation: application to BRCA2. Cancer Res. 2008 Jul 1;68(13):5023-30. Nicchia E et al. Identification of point mutations and large intragenic deletions in Fanconi anemia using next-generation sequencing technology. Mol Genet Genomic Med. 2015 Jul 2;3(6):500-12. Riahi A et al. Mutation spectrum and prevalence of BRCA1 and BRCA2 genes in patients with familial and early-onset breast/ovarian cancer from Tunisia. Clin Genet. 2015 Feb;87(2):155-60. Tram E et al. Missense variants of uncertain significance (VUS) altering the phosphorylation patterns of BRCA1 and BRCA2. PLoS One. 2013 May 21;8(5):e62468.
Color Diagnostics, LLC DBA Color Health	RCV000131346	SCV000902771	benign	Hereditary cancer-predisposing syndrome	2016-05-30	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV000195340	SCV002025884	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000045908	SCV002069478	uncertain significance	not specified	2018-09-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131346	SCV002532067	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	curation
Revvity Omics, Revvity	RCV000513762	SCV004234658	uncertain significance	not provided	2023-04-19	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077478	SCV000109276	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2008-06-05	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077478	SCV000145724	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357526	SCV001553023	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Pro3292Leu variant was identified in 6 of 7398 proband chromosomes (frequency: 0.0008) from individuals or families with breast, ovarian or pancreatic cancer and was not identified in 874 control chromosomes from healthy individuals (Borg 2010, Capanu 2011, Francies 2015, Riahi 2015, Takeuchi 2018). The variant was also identified in dbSNP (ID: rs56121817) as "With other allele", ClinVar (classified as benign by Invitae; as likely benign by GeneDx, SCRP and three other submitters; as uncertain significance by six submitters), LOVD 3.0 (8x), and in UMD-LSDB (14X as unclassified variant). The variant was identified in control databases in 20 of 245936 chromosomes at a frequency of 0.00008 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 5478 chromosomes (freq: 0.0004), Latino in 2 of 33562 chromosomes (freq: 0.00006), European in 6 of 111458 chromosomes (freq: 0.00005), Ashkenazi Jewish in 1 of 9844 chromosomes (freq: 0.0001), East Asian in 9 of 17246 chromosomes (freq: 0.0005), while the variant was not observed in the African, Finnish, and South Asian populations. In function studies Huci et al found that the p.Pro3292Leu variant was not sensitive to mitomycin C and etoposide induced DNA damage compared to wildtype unlike a truncating variant that was studied, moreover BRCA2/RAD51 foci formed normally with the variant present suggesting that the variant does not have clinical significance (Huci 2008). However, based on the location of the variant it is predicted to disrupt the sequence motif of the CDK2 kinase and affects interaction with RAD51 (Krassowski 2018, Tram 2013). Although the p.Pro3292 residue is not conserved in mammals and other organisms, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250524	SCV002520851	uncertain significance	Familial cancer of breast		no assertion criteria provided	literature only
Department of Medical and Surgical Sciences, University of Bologna	RCV000077478	SCV004228306	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BS1(Strong)+BS3(Strong)+BP1(Strong)+BP5(Very Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)
BRCAlab, Lund University	RCV000077478	SCV004243885	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing