Submissions for variant NM_000059.4(BRCA2):c.9116C>T (p.Pro3039Leu)

dbSNP: rs80359167

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045720	SCV000073733	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131718	SCV000186757	likely benign	Hereditary cancer-predisposing syndrome	2018-10-10	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	RCV000254649	SCV000210680	likely benign	not specified	2018-02-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Michigan Medical Genetics Laboratories, University of Michigan	RCV000083154	SCV000267827	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2016-04-21	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000254649	SCV000593758	likely benign	not specified	2016-04-19	criteria provided, single submitter	clinical testing
Mendelics	RCV000045720	SCV000838895	benign	Hereditary breast ovarian cancer syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759684	SCV000889172	likely benign	not provided	2023-01-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131718	SCV000910794	benign	Hereditary cancer-predisposing syndrome	2016-07-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000254649	SCV000917011	benign	not specified	2022-03-27	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9116C>T (p.Pro3039Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. Functional studies confirm these predictions indicating this variant has no effect on mRNA splicing (e.g. Caux-Moncoutier_2009, Houdayer_2012, Menendez_2012, Colombo_2013). The variant allele was found at a frequency of 8.9e-05 in 248254 control chromosomes (gnomAD). This frequency is not higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (8.9e-05 vs 0.00075), allowing no conclusion about variant significance. c.9116C>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Coulet_2010, Azzollini_2016, Rodriguez-Balada_2016, Park_2017, Guo_2020) but it was also reported in controls (Guo_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with BRCA2 pathogenic variants have been observed at our laboratory and in the literature (BRCA2 c.658_659delGT, p.Val220IlefsX4 at our laboratory; BRCA2 c.2808_2811delACAA, p.Ala938ProfsX21 in Santonocito_2020), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function through utilization of a homologous recombination DNA-repair activity assay, determined the variant to be neutral (example, Guidugli_2018, Hart_2019, Richardson_2021). HDR assays qualify as a recognized gold standard on the basis of updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) working group. This working group has recommended strong functional evidence (ACMG BS3) as sufficient weightage for categorization as likely benign (Tavtigian_2018). Multiple ClinVar submitters (evaluation after 2014) cite the variant with a predominant consensus as as benign/likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759684	SCV002047931	uncertain significance	not provided	2021-02-12	criteria provided, single submitter	clinical testing	The BRCA2 c.9116C>T; p.Pro3039Leu variant (rs80359167) is reported in the literature in individuals affected with breast and ovarian cancer, but without clear association with disease (Azzollini 2016, Jarhelle 2017, Park 2017). This variant is also reported in ClinVar (Variation ID: 52753), and is found in the general population with an overall allele frequency of 0.0089% (22/248254 alleles) in the Genome Aggregation Database. The proline at codon 3039 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.349). In vitro assays show a neutral effect on homology directed repair activity (Guidugli 2018). Other computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site, but in vitro functional studies show no effect on splicing (Colombo 2013, Menendez 2012). However, given the lack of clear clinical data, the clinical significance of the p.Pro3039Leu variant is uncertain at this time. References: Azzollini et al. Mutation detection rates associated with specific selection criteria for BRCA1/2 testing in 1854 high-risk families: A monocentric Italian study. Eur J Intern Med. 2016 Jul;32:65-71. Colombo M et al. Comparative in vitro and in silico analyses of variants in splicing regions of BRCA1 and BRCA2 genes and characterization of novel pathogenic mutations. PLoS One. 2013;8(2):e57173. 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. Jarhelle E et al. Characterization of BRCA1 and BRCA2 variants found in a Norwegian breast or ovarian cancer cohort. Fam Cancer. 2017 Jan;16(1):1-16. Menendez M et al. Assessing the RNA effect of 26 DNA variants in the BRCA1 and BRCA2 genes. Breast Cancer Res Treat. 2012 Apr;132(3):979-92. Park et al. Identification of a Novel BRCA1 Pathogenic Mutation in Korean Patients Following Reclassification of BRCA1 and BRCA2 Variants According to the ACMG Standards and Guidelines Using Relevant Ethnic Controls. Cancer Res Treat. 2017 Oct;49(4):1012-1021.
Sema4, Sema4	RCV000131718	SCV002532008	likely benign	Hereditary cancer-predisposing syndrome	2021-04-21	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000759684	SCV004132997	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	BRCA2: BP4, BS3:Supporting
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000045720	SCV005045475	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-22	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083154	SCV000115228	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2013-06-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083154	SCV000147542	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Department of Medical Genetics, University Hospital of North Norway	RCV000083154	SCV000301455	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355960	SCV001550996	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BRCA2 p.Pro3039Leu variant was identified in 8 of 6754 proband chromosomes (frequency: 0.001) from individuals or families with hereditary breast and ovarian cancer and was not identified in 1586 control chromosomes from healthy individuals (Park 2017, Azzollini 2016, Rodriguez-Balada 2016, Jarhelle 2016, Llort 2002). The variant was identified in dbSNP (rs80359167) as “with likely benign, uncertain significance allele”, ClinVar (classified as likely benign by Invitae, GeneDx, Ambry Genetics and 7 other submitters, uncertain significance by BIC and 1 other submitter and benign by Color), LOVD 3.0 (observed 9x) and UMD-LSDB (observed 19x). The variant was identified in control databases in 22 of 248,254 chromosomes at a frequency of 0.00009 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: South Asian in 6 of 30,496 chromosomes (freq: 0.0002), Latino in 6 of 34,364 chromosomes (freq: 0.0002), African in 2 of 16,040 chromosomes (freq: 0.0001), European in 8 of 111,594 chromosomes (freq: 0.00007); it was not observed in the Ashkenazi Jewish, East Asian, Finnish, and Other populations. The variant was observed in UMD-LSDB in a sample with a co-occurring BRCA1 pathogenic variant (c.670+1G>T). In cDNA amplification assays, the variant had no observed effect on in vitro splicing (Rodriguez-Balada 2016, Colombo 2012, Houdayer 2012, Menedez 2012). The p.Pro3039 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Pro3039Leu variant occurs in the first base of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% 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.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000759684	SCV001906374	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000759684	SCV001969091	uncertain significance	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000083154	SCV004243853	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing